Nsd family inhibitors and methods of treatment therewith

ABSTRACT

Provided herein are small molecule inhibitors of NSD1, NSD2 and/or NSD3 activity, and methods of use thereof for the treatment of disease, including leukemia, breast cancer, osteosarcoma, lung and prostate cancers and other solid tumors as well as other diseases dependent on the activity of NSD1, NSD2 and/or NSD3.

CROSS-REFRENCE TO RELATED APPLICATION

The present invention is a continuation of U.S. patent application Ser.No. 16/213,564, filed Dec. 7, 2018, which claims the priority benefit ofU.S. Provisional Patent Applications 62/595,616, filed Dec. 7, 2017, and62/595,617, filed Dec. 7, 2017, each of which are incorporated byreference in its entirety.

FIELD

Provided herein are small molecule inhibitors of NSD1, NSD2 and/or NSD3activity, and methods of use thereof for the treatment of disease,including leukemia, breast cancer, osteosarcoma, lung and prostatecancers and other solid tumors as well as other diseases dependent onthe activity of NSD1, NSD2 and/or NSD3.

BACKGROUND

Nuclear Receptor Binding SET Domain Protein 1 (NSD1) is a member ofnuclear receptor binding SET domain (NSD) family of proteins. Thisfamily contains three methyltransferases: NSD1, NSD2 (also calledMMSET/WHSC1) and NSD3 (WHSC1L1), which are key enzymes involved indi-methylation of H3K36 (Refs. 2, 3; incorporated by reference in theirentireties), a histone mark that is most commonly associated with thetranscription of active euchromatin (Ref. 2; incorporated by referencein its entirety). Growing number of studies link NSD methyltransferasesto a variety of diseases and cancers (Ref. 6; incorporated by referencein its entirety). Translocation of NSD1 leading to Nup98-NSD1 fusionprotein has been found in acute leukemia (Refs. 1, 7-10; incorporated byreference in their entireties), and activity of NSD1 has been implicatedin lung (Ref. 11; incorporated by reference in its entirety)] andprostate cancers (Ref. 12; incorporated by reference in its entirety).NSD2/MMSET is overexpressed in a variety of cancers (Refs. 13, 14;incorporated by reference in their entireties), and the t(4;14)(p16;q23)translocation involving NSD2 is found in a subgroup of multiple myelomapatients with very poor prognosis (Refs. 15, 16; incorporated byreference in their entireties). In addition, NSD2 is expressed at highlevels in metastatic prostate cancer and knockdown of NSD2 by shRNAreduces cell proliferation and invasion in prostate cancer cells (Ref.17; incorporated by reference in its entirety). Furthermore,amplifications of NSD3 are observed in breast cancers (Ref. 18;incorporated by reference in its entirety), osteosarcoma, and NSD3fusion transcripts were found in hematological malignancies (Ref. 19;incorporated by reference in its entirety). The need to developinhibitors of the NSD family of HMT-ases has been emphasized in severalreports (Ref. 20-22; incorporated by reference in their entireties).

Translocation t(5;11)(q35;p15.5) creates a fusion of Nucleoporin 98(Nup98) gene with NSD1 and is found in acute myeloid leukemia (AML)patients with very poor prognosis (Refs. 1, 7-10; incorporated byreference in its entirety). Analysis of a large cohort of leukemiapatients revealed that Nup98-NSD1 translocation is present in 16% ofcytogenetically normal pediatric AML patients and in 2% adult AMLs(FIGS. 1A,B) (Ref. 1; incorporated by reference in its entirety). Thepresence of Nup98-NSD1 translocation confers a poor outcome and despiteintensive treatment, AML patients with Nup98-NSD1 are refractory toinduction chemotherapy or relapse within first year of diagnosis (Ref.1; incorporated by reference in its entirety), emphasizing the urgentneed for new therapeutics.

Nup98-NSD1 is a very potent oncogene capable of inducing leukemia invivo in mice (Ref. 5; incorporated by reference in its entirety).Interestingly, more than 70% of patients with Nup98-NSD1 haveco-existing FLT3-ITD activating mutations (Ref. 4; incorporated byreference in its entirety). This finding led to the development ofaggressive mice model of Nup98-NSD1/FLT3-ITD leukemia (FIG. 1C). Becauseof short latency, the Nup98-NSD1/FLT3-ITD model is suitable for efficacystudies to test NSD1 inhibitors.

Transforming properties of Nup98-NSD1 oncogene have been extensivelycharacterized (Ref. 5; incorporated by reference in its entirety).Transduction with Nup98-NSD1 immortalizes bone marrow progenitor cells,sustains self-renewal and up-regulates expression of Hox-A cluster genesand Meis1 (Ref. 5; incorporated by reference in its entirety).Mechanistically, Nup98-NSD1 binds genomic elements adjacent to HoxA 7and HoxA9 and maintains histone H3K36 di-methylation. Deletion of SETdomain or point mutations abrogating the catalytic activity of SETdomain abolished transforming potential of Nup98-NSD1 (FIG. 1D),demonstrating that the oncogenic activity of Nup98-NSD1 is dependent onthe histone-methyltransferase activity of NSD1 SET domain

SUMMARY

Provided herein are small molecule inhibitors of NSD1, NSD2 and/or NSD3activity, and methods of use thereof for the treatment of disease,including leukemia, breast cancer, osteosarcoma, lung and prostatecancers and other solid tumors as well as other diseases dependent onthe activity of NSD1, NSD2 and/or NSD3.

In some embodiments, provided herein are compounds comprising astructure of Formula (I):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁶ is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, hydroxy, alkoxy, amine, alkylamine, alkenamine,aklynamine, thiol, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,thiocyanate, phosphine oxide (e.g., dialkylphosphine oxide), acarbocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring,carbocyclic or heterocyclic aromatic ring fused to another aromaticring, a hydrogen bond donor, a hydrogen bond acceptor, and combinationsthereof; and

wherein R⁷ is H, D, F, OH, NH₂, CH₃;

In some embodiments, provided herein are compounds comprising astructure of Formula (IIa):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein L¹ and L² are independently 1-8 member aliphatic carbon linkers,optionally comprising one or more heteroatoms (e.g., O, N, or S) and/orone or more double or triple bonds; L¹ or L² may be present or absent.

wherein A is an aryl, heteroaryl (e.g., monocyclic (e.g., 4-member ring,5-member ring, 6-member ring, 7-member ring, etc.) bicyclic, etc.),cycloalkyl (e.g., 4-member ring, 5-member ring, 6-member ring, 7-memberring, etc.), or heterocycle (e.g., 4-member ring, 5-member ring,6-member ring, 7-member ring, etc.); see Table 1 for examples of ringstructures;

wherein A is unsubstituted or substituted (e.g., one or more alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof)

wherein Y is a Michael acceptor (e.g., propenal, 3-buten-2-one,acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate,propenanamide, propenenitrile, nitroethylene, etc.); Y may be present orabsent

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIb):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein Z is NH, S, O, CH₂, or is absent (e.g., a direct covalent bondbetween A and terminal CH₂ group of the scaffold);

wherein A is an aryl, heteroaryl (e.g., monocyclic (e.g., 4-member ring,5-member ring, 6-member ring, 7-member ring, etc.) bicyclic, etc.),cycloalkyl (e.g., 4-member ring, 5-member ring, 6-member ring, 7-memberring, etc.), or heterocycle (e.g., 4-member ring, 5-member ring,6-member ring, 7-member ring, etc.); see Table 1 for examples of ringstructures;

wherein A is unsubstituted or substituted (e.g., one or more alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof)

wherein L and is a 1-8 member aliphatic carbon linker, optionallycomprising one or more heteroatoms (e.g., O, N, or S) and/or one or moredouble or triple bonds; L may be present or absent;

wherein Y is a Michael acceptor (e.g., propenal, 3-buten-2-one,acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate,propenanamide, propenenitrile, nitroethylene, etc.); Y may be present orabsent

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIc):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein Z is NH, S, O, CH₂, or is absent (e.g., a direct covalent bondbetween A and terminal CH₂ group of the scaffold);

wherein R⁸ is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein L is a 1-8 member aliphatic carbon linker, optionally comprisingone or more heteroatoms (e.g., O, N, or S) and/or one or more double ortriple bonds; L may be present or absent

wherein Y is a Michael acceptor (e.g., propenal, 3-buten-2-one,acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate,propenanamide, propenenitrile, nitroethylene, etc.); Y may be present orabsent

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (IId):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein Z is NH, S, O, CH₂, or is absent (e.g., a direct covalent bondbetween A and terminal CH₂ group of the scaffold);

wherein A is an aryl, heteroaryl (e.g., monocyclic (e.g., 4-member ring,5-member ring, 6-member ring, 7-member ring, etc.) bicyclic, etc.),cycloalkyl (e.g., 4-member ring, 5-member ring, 6-member ring, 7-memberring, etc.), or heterocycle (e.g., 4-member ring, 5-member ring,6-member ring, 7-member ring, etc.); see Table 1 for examples of ringstructures;

wherein A is unsubstituted or substituted (e.g., one or more alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof)

wherein L is absent (e.g., a direct covalent bond between A and E), oris a 1-8 member aliphatic carbon linker, optionally comprising one ormore heteroatoms (e.g., O, N, or S) and/or one or more double or triplebonds;

wherein E is an aryl, heteroaryl (e.g., monocyclic (e.g., 4-member ring,5-member ring, 6-member ring, 7-member ring, etc.) bicyclic, etc.),cycloalkyl (e.g., 4-member ring, 5-member ring, 6-member ring, 7-memberring, etc.), or heterocycle (e.g., 4-member ring, 5-member ring,6-member ring, 7-member ring, etc.);

wherein E is unsubstituted or substituted (e.g., one or more alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof)

wherein Y is a Michael acceptor (e.g., propenal, 3-buten-2-one,acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate,propenanamide, propenenitrile, nitroethylene, etc.);

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIe):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein Z is NH, S, O, CH₂, or is absent (e.g., a direct covalent bond);

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein L and is a 1-8 member aliphatic carbon linker, optionallycomprising one or more heteroatoms (e.g., O, N, or S) and/or one or moredouble or triple bonds;

wherein A is an aryl, heteroaryl (e.g., monocyclic (e.g., 4-member ring,5-member ring, 6-member ring, 7-member ring, etc.) bicyclic, etc.),cycloalkyl (e.g., 4-member ring, 5-member ring, 6-member ring, 7-memberring, etc.), or heterocycle (e.g., 4-member ring, 5-member ring,6-member ring, 7-member ring, etc.); see Table 1 for examples of ringstructures;

wherein A is unsubstituted or substituted (e.g., one or more alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof)

wherein Y is a Michael acceptor (e.g., propenal, 3-buten-2-one,acrylamide, vinyl sulfonamide, propynamide, ethyl propenoate,propenanamide, propenenitrile, nitroethylene, etc.);

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (III):

or a salt thereof;

wherein X is CH₂ or NH;

wherein R² is selected from H, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclic ring, anaromatic ring, a substituted aromatic ring, a heterocyclic aromaticring, a substituted heterocyclic aromatic ring, a substituted ornon-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁴ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano,sulfonyl, phosphine oxide, a hydrogen bond donor, a hydrogen bondacceptor, and combinations thereof;

wherein R⁵ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R⁶ is selected from H, alkyl, substituted alkyl, hydroxy,alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano,sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, an aryl ring, a substituted arylring, a heteroaryl ring, a substituted heteroaryl ring, and combinationsthereof; and

wherein R⁷ is H, D, F, OH, NH₂, CH₃.

In some embodiments, provided herein are compounds comprising astructure of Formula (IV):

or a salt thereof;

wherein X is CH₂ or NH;

wherein G is —(CH₂)_(n)—S—S—(CH₂)_(m)—, wherein n and m areindependently 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6, or ranges therebetween);

wherein R^(2a) and R^(2b) are independently selected from H, alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide (e.g.,dialkylphosphine oxide), a carbocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof;

wherein R^(4a) and R^(4b) are independently selected from H, alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, haloalkyl, amide, cyano, sulfonyl, phosphine oxide, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof;

wherein R^(7a) and R^(7b) are H, D, F, OH, NH₂, CH₃.

In some embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R² (or R^(2a) or R^(2b)) is afunctional group selected from H, alkyl, substituted alkyl, branchedalkyl, a substituted branched alkyl (e.g. halogen substituted branchedalkyl) alkene, substituted alkene, alkyne, substituted alkene, hydroxy,alkoxy, amine, substituted amine (e.g. alkyl substituted amine),thioalkyl, halogen, ketone, amide, a substituted amide, cyano, sulfonyl,carboxy, dialkylphosphine oxide, a carbocyclic ring, a substitutedcarobocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring (e.g.piperidine, tetrahydropyran, alkylsulfonyl substituted piperidine,sulfonamide substituted piperidine, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof.

In some embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R⁴ (or R^(4a) or R^(4b)) is afunctional group selected from H, CH₃, (CH₂)₁₋₂CH₃, CH═CH₂, CH═CHCH₃,CH₂CH═CH₂, OH, (CH₂)₁₋₂OH, OCH₃, OCH₂CH₃, CH₂OCH₃, NH₂, (CH₂)₁₋₂NH₂,NHCH₂CH₃, NHCH₃, CH₂NHCH₃, SH, (CH₂)₁₋₂SH, SCH₃, CH₂SCH₃, Cl, Br, F, I,(CH₂)₁₋₂Cl, (CH₂)₁₋₂Br, (CH₂)₁₋₂F, (CH₂)₁₋₂I, CF₃, CFH₂, CF₂H, CBr₃,CCl₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃, CH₂Cl₃, CN, and combinations thereof.

In some embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R⁵ (or R^(5a) or R^(5b)) is afunctional group selected from H, alkyl, substituted alkyl, branchedalkyl, a substituted branched alkyl (e.g. halogen substituted branchedalkyl) alkene, substituted alkene, alkyne, substituted alkene, hydroxy,alkoxy, amine, substitutes amine, thioalkyl, halogen, ketone, amide, asubstituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, acarbocyclic ring, a substituted carobocyclic ring, an aromatic ring, asubstituted aromatic ring, a heterocyclic aromatic ring, a substitutedheterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring (e.g. piperidine, tetrahydropyran,alkylsulfonyl substituted piperidine, sulfonamide substitutedpiperidine), carbocyclic or heterocyclic aromatic ring fused to anotheraromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof.

In some embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R⁶ (or R^(6a) or R^(6b)) is afunctional group selected from H, alkyl, substituted alkyl, branchedalkyl, a substituted branched alkyl (e.g. halogen substituted branchedalkyl), alkene, substituted alkene, alkyne, substituted alkene, hydroxy,alkoxy, amine, substitutes amine, thioalkyl, thiol, halogen, ketone,amide, a substituted amide, cyano, sulfonyl, carboxy, dialkylphosphineoxide, a carbocyclic ring, saturated ring comprising 3-7 atoms (C, N,O), a substituted carobocyclic ring, an aromatic ring, a substitutedaromatic ring, a heterocyclic aromatic ring, a substituted heterocyclicaromatic ring, a substituted or non-substituted heterocyclicnon-aromatic ring (e.g. piperidine, tetrahydropyran, alkylsulfonylsubstituted piperidine, sulfonamide substituted piperidine), carbocyclicor heterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof.

In some embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R⁷ (or R^(7a) or R^(7b)) isH. In other embodiments, for a compound of one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), R⁷ (or R^(7a) or R^(7b)) is afunctional group selected from H, D, CH₃, (CH₂)CH₃, CH═CH₂, OH, CH₂OH,OCH₃, NH₂, CH₂NH₂, NHCH₃, SH, CH₂SH, SCH₃, Cl, Br, F, I, CH₂Cl, CH₂Br,CH₂F, CH₂I, CF₃, CBr₃, CCl₃, Cl₃, CH₂CF₃, CH₂CBr₃, CH₂CCl₃, CH₂Cl₃, CN,and combinations thereof.

In some embodiments, any of the R² (or R^(2a) or R^(2b)), R⁴ (or R^(4a)or R^(4b)), R⁵ (or R^(5a) or R^(5b)), and/or R⁷ (or R^(7a) or R^(7b))substituents, when present in a compound of any one of Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV) are of one of Formulas(a)-(q):

wherein one of J, Q¹, or J¹, when present, is linked to thebenzothiazole ring at the appropriate position (e.g., 2, 5, and/or 6);

wherein each J, J¹, J², J³, and J⁴, when present, are independentlyselected from the group consisting of: a covalent bond, H, alkyl₁₋₁₅,alkenyl₁-6, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH,(CH₂)₀₋₆C(O)NH(CH₂)₁₋₆, (CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl,sulfonamide, alkylsulfonamide, (CH₂)₀₋₆C(S)NH(CH₂)₁₋₆,(CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH,(CH₂)₀₋₆NH(CH₂)₁₋₆, (CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆ (See, e.g., Compound 80),(CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(PH)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, (CH₂O)₁₋₆, and trimethylmethane;

wherein each Q, Q¹, and Q², when present, is independently selected fromthe group consisting of: furan, benzofuran, isobenzofuran, pyrrole,indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene,imidazole, benzimidazole, purine, pyrazole, indazole, oxazole,benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,benzene, napthalene, pyridine, quinolone, isoquinoline, pyrazine,quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline,phthalazine, thalidomide, triazine (e.g., 1,2,3-triazine;1,2,4-triazine; 1,3,5 triazine), thiadiazole, aziridine, thiirane(episulfides), oxirane (ethylene oxide, epoxides), oxaziridine,dioxirane, azetidine, oxetan, thietane, diazetidine, dioxetane,dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine,pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,dioxolane, dithiolane, piperidine, oxane, thiane, pepierazine,morpholine, thiomorpholine, dioxane, dithiane, trioxane, thithiane,azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran,cyclobutene, cyclopentene, cyclohexene, cycloheptene,1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, any suitable C³-C⁷ cycloalkylgroup, and any of the ring structures depicted in Table 1;

wherein each Q, Q¹, and Q², when present, may display one or moreadditional J groups at any position on the Q ring;

wherein any alkyl or (CH₂)_(x-y) groups above may be straight orbranched;

wherein any alkyl or (CH₂)_(x-y) groups above may additionally compriseOH, ═O, NH₂, CN, dihaloalkyl (e.g., CF₂H), trihaloalkyl (e.g., CF₃), orhalogen (e.g., F) substituents at one or more carbons;

wherein the number of hydrogens on terminal positions of the groupsabove may be adjusted if the group is linked to an additional group(e.g., CH₃ adjusted to CH₂, OH adjusted to O, etc.) or if the group isterminal (e.g., CH₂ adjusted to CH₃, O adjusted to OH, etc.); and

wherein any of formulas (a-q) may additionally comprise a terminalfluorophore (e.g. fluoresceine), solid surface, enzyme ligand (e.g.thalidomide or VHL ligand (e.g.,(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,or affinity tag (e.g. biotin).

In some embodiments, any A-ring or E-ring present in a structure may beselected from the exemplary rings depicted in Table 1. Such rings may beattached to the structure at any suitable positions on the exemplaryrings.

TABLE 1 Non-limiting examples of Ring A or Ring E structures Ring ANumber Ring A Structure   A-1 

A-2 

A-3 

A-4 

A-5 

A-6 

A-7 

A-8 

A-9 

A-10

A-11

A-12

A-13

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

A-33

A-34

A-35

A-36

A-37

A-38

A-39

A-40

A-41

A-42

A-43

A-44

A-45

A-46

A-47

A-48

A-49

A-50

A-51

A-52

A-53

A-54

A-55

A-56

A-57

A-58

A-59

A-60

A-61

A-62

A-63

A-64

A-65

A-66

A-67

A-68

A-69

A-70

A-71

A-72

A-73

A-74

A-75

A-76

A-77

A-78

A-79

A-80

A-81

A-82

A-83

A-84

A-85

A-86

A-87

A-88

A-89

A-90

A-91

A-92

A-93

A-94

A-95

A-96

A-I  

A-I-2 

A-I-3 

A-I-4 

A-I-5 

A-I-6 

A-I-7 

A-I-8 

A-I-9 

A-I-10

A-I-11

A-I-12

A-I-13

A-I-14

A-I-15

A-I-16

A-I-17

A-I-18

A-I-19

A-I-20

A-I-21

A-I-22

A-I-23

A-I-24

A-II  

A-II-2 

A-II-3 

A-II-4 

A-II-5 

A-II-6 

A-II-7 

A-II-8 

A-II-9 

A-II-10

A-II-11

A-II-12

A-II-13

A-II-14

A-II-15

A-II-16

A-II-17

A-II-18

A-II-19

A-II-20

A-II-21

A-II-22

A-II-23

A-II-24

A-II-25

A-II-26

A-II-27

A-II-28

A-II-29

A-II-30

A-II-31

A-II-32

A-II-33

A-II-34

A-II-35

A-II-36

A-II-37

A-II-38

A-II-39

A-II-40

A-II-41

A-II-42

A-II-43

A-III  

A-III-2 

A-III-3 

A-III-4 

A-III-5 

A-III-6 

A-III-7 

A-III-8 

A-III-9 

A-III-10

A-III-11

A-III-12

A-III-13

A-IV  

A-IV-2 

A-IV-3 

A-IV-4 

A-IV-5 

A-IV-6 

A-IV-7 

A-IV-8 

A-IV-9 

A-IV-10

A-IV-11

A-IV-12

A-IV-13

A-IV-14

A-IV-15

A-IV-16

A-IV-17

A-IV-18

A-IV-19

A-IV-20

A-IV-21

A-IV-22

A-IV-23

A-IV-24

*wherein R, when present on a structure of Table 1, is any suitablesubstituent described herein, such as, alkyl, substituted alkyl,hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone, amide,cyano, sulfonyl, phosphine oxide (e.g., dialkylphosphine oxide), acarbocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring,carbocyclic or heterocyclic aromatic ring fused to another aromaticring, a hydrogen bond donor, a hydrogen bond acceptor, and combinationsthereof. **wherein Z, when present on a structure of Table 1, is N (orNH), CH (or CH₂), O, or S, when suitable for the selected structure.

An A-ring and/or E-ring may, in some embodiments, comprise a multi-ringsystem, such as A-I through A-IV-24 depicted in Table 1. Examples ofcompounds comprising a bicyclic A-ring include compounds 274, 275, and306-311. In some embodiments, compounds within the scope herein maycomprise the bicyclic A-rings of Compounds 274, 275, and 306-311. Suchbicyclic rings may be attached to the structure at any suitablepositions on the exemplary rings.

In some embodiments, any A-ring or E-ring present in a structure may befurther substituted at any position(s), for example, with one or morefunction groups selected from the list consisting of alkyl₁₋₅,alkenyl₁₋₆, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH,(CH₂)₀₋₆C(O)NH(CH₂)₁₋₆, (CH₂)₀₋₆NHC(O)(CH₂)₁₋₆, alkylsulfonyl,sulfonamide, alkylsulfonamide, (CH₂)₀₋₆C(S)NH(CH₂)₁₋₆,(CH₂)₀₋₆O(CH₂)₁₋₆, (CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH,(CH₂)₀₋₆NH(CH₂)₁₋₆, (CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆ (See, e.g., Compound 80),(CH₂)₀₋₆NH₂, (CH₂)₀₋₆SO₂(CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆, (CH₂)₀₋₆SO₂NH₂, halogen (e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(Ph)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀-3NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, (CH₂₀)₁₋₆, and trimethylmethane.

In some embodiments, the compound is selected from any of the compoundsdepicted in Table 2. In some embodiments, a compound is of one orFormulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV) anddisplays any suitable combination of the substituents depicted in thecompounds of Table 2.

In some embodiments, provided herein are pharmaceutical compositionscomprising a compound of any one of the preceding claims and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition is formulated for oral administration. Insome embodiments, the pharmaceutical composition is formulated forinjection.

In some embodiments, provided herein are methods of inhibiting theactivity of NSD1, NSD2 or NSD3 comprising contacting NSD1, NSD2 or NSD3with an effective amount of a compound described herein. In someembodiments, contacting comprises contacting a cell that expresses NSD1,NSD2 or NSD3.

In some embodiments, provided herein are methods of treating a disease,comprising administering to a subject a pharmaceutical compositiondescribed herein in an amount effective to inhibit the activity of NSD1,NSD2 or NSD3. In some embodiments, the disease is a cancer. In someembodiments, the disease is a proliferative disorder. In someembodiments, the pharmaceutical composition is co-administered with anadditional cancer therapeutic. In some embodiments, the subject is ahuman.

In some embodiments, provided herein is the use of a compound describedherein. In some embodiments, provided herein is the use of a compounddescribed herein for inhibiting NSD1, NSD2 or NSD3 activity. In someembodiments, provided herein is the use of a compound described hereinfor the treatment of a disease (e.g., cancer).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . Nup98-NSD1 is a potent oncogene expressed in AML patients withpoor prognosis. Incidence of Nup98-NSD1 leukemia in pediatric (A) andadult (B) AML (Ref. 1; incorporated by reference in its entirety). (C)FLT3-ITD cooperates with Nup98-NSD1 and accelerates development ofleukemia in mice (Ref. 4; incorporated by reference in its entirety).(D) Point mutations in NSD1 SET domain abolish transforming propertiesof Nup98-NSD1 (Ref. 5; incorporated by reference in its entirety).

FIG. 2A-B. A. Irreversible binding of 151 to NSD1 detected by MS. 10 μM151 was incubated with NSD1 for 20 h. B. HSQC spectrum of 150 μM NSD1with 300 μM 151. Several perturbed residues are labeled, includingCys2062.

FIG. 3A-B. Compound 159 binds covalently to NSD1 and engages NSD1 incells. A. Mass spectrometry experiment showing covalent engagement ofNSD1 by 159. 6 μM of 159 was incubated with 1 mM of NSD1 SET domain for8 hours. B. CETSA assay showing stabilization of NSD1 (1753-2095fragment) by treatment of HeLa cells with 5 μM 159.

FIG. 4 . MTT assay showing time-dependent (3, 7 and 10 days) growthinhibition of Nup98-NSD1 cells by 159 (left). 159 does not inhibitproliferation of control HM-2 cells (right).

FIG. 5A-B. Mechanism of action of 159 in cells. A. Gene expressionanalysis using qRT-PCR for Nup98-NSD1 cells treated with 159 for 4 days.B. Cytospins showing differentiation of Nup98-NSD1 cells induced by 159.

FIG. 6A-F. Pharmacokinetics and efficacy of 159 in Nup98-NSD1 leukemiamodel. A. Pharmacokinetics studies in mice treated with 25 mg/kg of 159using I.P. administration. B. Efficacy in Nup98-NSD1 subcutaneous model.Mice were treated with 25 mg/kg q.d., I.P. C. Representative tumors fromvehicle and 159 treated mice. D. Treatment reduced expression of Hoxa7in tumors from 159 treated mice E. Immuno-histochemistry analysis ofH3K36me2 level in tumor samples of mice treated with vehicle (top) and159 (bottom). Strong reduction of H3K36me2 level is observed. F. Bodyweight of 159 treated animals

FIG. 7A-C. Mass spectrometry data showing covalent engagement of 198with NSD1, NSD2 and NSD3. Asterisk denotes covalent protein adduct with198.

FIGS. 8A-B. Activity of NSD inhibitors in breast cancer cell lines. A. 7days treatment MTT viability data for cpd 230 in MCF7 (GI50=1.5 uM),ZR-57-1 (GI50=100 nM) and MDA-MB-468 (35 nM). B. 7 days treatmentviability data for cpd 225 in MCF7 (487 nM), ZR-75-1 (53 nM), SUM44 (341nM), MDA-MB-468 (GI50=31 nM).

DEFINITIONS

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsdescribed herein, some preferred methods, compositions, devices, andmaterials are described herein. However, before the present materialsand methods are described, it is to be understood that this invention isnot limited to the particular molecules, compositions, methodologies orprotocols herein described, as these may vary in accordance with routineexperimentation and optimization. It is also to be understood that theterminology used in the description is for the purpose of describing theparticular versions or embodiments only, and is not intended to limitthe scope of the embodiments described herein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. However, in case of conflict,the present specification, including definitions, will control.Accordingly, in the context of the embodiments described herein, thefollowing definitions apply.

As used herein and in the appended claims, the singular forms “a”, “an”and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an NSD1, NSD2 or NSD3inhibitor” is a reference to one or more NSD1, NSD2 or NSD3 inhibitorsand equivalents thereof known to those skilled in the art, and so forth.

As used herein, the term “comprise” and linguistic variations thereofdenote the presence of recited feature(s), element(s), method step(s),etc. without the exclusion of the presence of additional feature(s),element(s), method step(s), etc. Conversely, the term “consisting of”and linguistic variations thereof, denotes the presence of recitedfeature(s), element(s), method step(s), etc. and excludes any unrecitedfeature(s), element(s), method step(s), etc., except forordinarily-associated impurities. The phrase “consisting essentially of”denotes the recited feature(s), element(s), method step(s), etc. and anyadditional feature(s), element(s), method step(s), etc. that do notmaterially affect the basic nature of the composition, system, ormethod. Many embodiments herein are described using open “comprising”language. Such embodiments encompass multiple closed “consisting of”and/or “consisting essentially of” embodiments, which may alternativelybe claimed or described using such language.

All chemical names of substituents should be interpreted in light ofIUPAC and/or a modified format in which functional groups within asubstituent are read in the order in which they branch from the scaffoldor main structure. For example, in the modified nomenclature,methyl-sulfonyl-propanol refers to CH₂SO₂CH₂CH₂CH₂OH or:

As another example, according to the modified nomenclature, amethyl-amine substituent is:

while an amino-methyl substituent is:

All chemical names of substituents should be interpreted in light ofIUPAC and/or the modified nomenclature and with reference to thechemical structures depicted and/or described herein.

As used herein, the term “subject” broadly refers to any animal,including but not limited to, human and non-human animals (e.g., dogs,cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As usedherein, the term “patient” typically refers to a subject that is beingtreated for a disease or condition.

As used herein, the term “subject at risk for a disease,” for example,“a subject at risk for cancer” refers to a subject with one or more riskfactors for developing the disease (e.g., cancer). Depending upon thespecific disease, risk factors may include, but are not limited to,gender, age, genetic predisposition, environmental exposures,infections, and previous incidents of diseases, lifestyle, etc.

As used herein, the term “effective amount” refers to the amount of acomposition sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route.

As used herein, the terms “administration” and “administering” refer tothe act of giving a drug, prodrug, or other agent, or therapeutictreatment to a subject or in vivo, in vitro, or ex vivo cells, tissues,and organs. Exemplary routes of administration to the human body can bethrough space under the arachnoid membrane of the brain or spinal cord(intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical ortransdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear,rectal, vaginal, by injection (e.g., intravenously, subcutaneously,intratumorally, intraperitoneally, etc.) and the like.

As used herein, the terms “co-administration” and “co-administering”refer to the administration of at least two agent(s) (e.g., NSD1inhibitor and one or more additional therapeutics) or therapies to asubject. In some embodiments, the co-administration of two or moreagents or therapies is concurrent. In other embodiments, a firstagent/therapy is administered prior to a second agent/therapy. Those ofskill in the art understand that the formulations and/or routes ofadministration of the various agents or therapies used may vary. Theappropriate dosage for co-administration can be readily determined byone skilled in the art. In some embodiments, when agents or therapiesare co-administered, the respective agents or therapies are administeredat lower dosages than appropriate for their administration alone. Thus,co-administration is especially desirable in embodiments where theco-administration of the agents or therapies lowers the requisite dosageof a potentially harmful (e.g., toxic) agent(s), and/or whenco-administration of two or more agents results in sensitization of asubject to beneficial effects of one of the agents via co-administrationof the other agent.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invitro, in vivo or ex vivo.

The terms “pharmaceutically acceptable” or “pharmacologicallyacceptable,” as used herein, refer to compositions that do notsubstantially produce adverse reactions, e.g., toxic, allergic, orimmunological reactions, when administered to a subject.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers including, but not limitedto, phosphate buffered saline solution, water, emulsions (e.g., such asan oil/water or water/oil emulsions), and various types of wettingagents, any and all solvents, dispersion media, coatings, sodium laurylsulfate, isotonic and absorption delaying agents, disintigrants (e.g.,potato starch or sodium starch glycolate), and the like. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see, e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. (1975), incorporated herein by reference in its entirety.

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds herein are contemplated asbeing pharmaceutically acceptable. However, salts of acids and basesthat are non-pharmaceutically acceptable may also find use, for example,in the preparation or purification of a pharmaceutically acceptablecompound.

As used herein, the term “instructions for administering said compoundto a subject,” and grammatical equivalents thereof, includesinstructions for using the compositions contained in a kit for thetreatment of conditions (e.g., providing dosing, route ofadministration, decision trees for treating physicians for correlatingpatient-specific characteristics with therapeutic courses of action).

“Amino” refers to the —NH₂ moiety.

“Carbonyl” refers to a moiety of the formula —C(═O)—.

“Carboxy” or “carboxyl” refers to the —CO₂H moiety.

“Cyano” refers to the —CN moiety.

Hydroxy” or “hydroxyl” refers to the —OH moiety.

Imino” refers to the ═NH moiety. Unless stated otherwise specifically inthe specification, an imino group is optionally substituted.

“Nitro” refers to the —NO₂ moiety.

“Oxo” refers to the ═O moiety.

“Thioxo” refers to the ═S moiety.

“Acyl” refers to the group —C(═O)R_(a), where R_(a) is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon), heteroalkyl, and heterocyclylalkyl. Unless statedotherwise specifically in the specification, an acyl group is optionallysubstituted.

“Alkyl” refers to a straight or branched hydrocarbon chain moietyconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Alkyl includes alkenyls (one or more carbon-carbon double bonds)and alkynyls (one or more carbon-carbon triple bonds). Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted.

“Alkoxy” refers to a moiety of the formula —OR_(a) where R_(a) is analkyl group as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup is optionally substituted.

“Alkylamino” refers to a moiety of the formula —NHR_(a) or —NR_(a)R_(b)where R_(a) and R_(b) are each independently an alkyl group as definedherein containing one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group is optionallysubstituted.

“Alkylaminoalkyl” refers to an alkyl moiety comprising at least onealkylamino substituent. The alkylamino substituent can be on a tertiary,secondary or primary carbon. Unless stated otherwise specifically in thespecification, an alkylaminoalkyl group is optionally substituted.

“Amide” or “amido” refers to a moiety with formula —C(═O)NR_(a)R_(b) or—NR_(a)C(═O)R_(b), where R_(a) and R_(b) are each independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon), heteroalkyl, andheterocyclylalkyl, each of which moiety may itself be optionallysubstituted. In some embodiments, it is a C₁-C₄ amido or amide group,which includes the amide carbonyl in the total number of carbons in thegroup. The R_(a)R_(b) of —NR_(a)R_(b) of the amide may optionally betaken together with the nitrogen to which it is attached to form a 4-,5-, 6-, or 7-membered ring. Unless stated otherwise specifically in thespecification, an amido group is optionally substituted.

“Aminoalkyl” refers to an alkyl moiety comprising at least one aminosubstituent. The amino substituent can be on a tertiary, secondary orprimary carbon. Unless stated otherwise specifically in thespecification, an aminoalkyl group is optionally substituted.

“Aminocarbonyl” refers to an amide moiety of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H oralkyl. Unless stated otherwise specifically in the specification, anaminocarbonyl group is optionally substituted.

“Aryl” refers to a hydrocarbon ring system moiety comprising 6 to 18carbon atoms and at least one aromatic ring. For purposes of thisinvention, the aryl moiety is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl moieties include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant toinclude aryl groups that are optionally substituted.

“Aralkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined herein and R_(c) is one or more arylmoieties as defined herein, for example, benzyl, diphenylmethyl, and thelike. Unless stated otherwise specifically in the specification, anaralkyl group is optionally substituted.

“Aralkylamino” refers to a aralkyl-NR_(a)— moiety, where R_(a) is H oralkyl. Unless stated otherwise specifically in the specification, anaralkylamino is optionally substituted.

“Aralkyloxy” refers to an aralkyl-O— moiety. Unless stated otherwisespecifically in the specification, an aralkyloxy is optionallysubstituted.

“Arylamino” refers to a —NR_(a)-aryl moiety, where R_(a) is H or alkyl.Unless stated otherwise specifically in the specification, an arylaminois optionally substituted.

“Aryloxy” refers to an —O-aryl moiety. Unless stated otherwisespecifically in the specification, an aryloxy is optionally substituted.

“Bicycloalkyl” refers to a moiety with two cycloalkyl moieties, thathave two or more atoms in common. If the cycloalkyl moieties haveexactly two adjacent atoms in common they are said to be “fused”.Examples include, but are not limited to, bicyclo[3.1.0]hexyl,perhydronaphthyl, and the like. If the cycloalkyl moieties have morethan two atoms in common they are said to be “bridged”. Examplesinclude, but are not limited to, adamantyl, bicyclo[3.2.1]heptyl(“norbornyl”), bicyclo[2.2.2]octyl, and the like. Unless statedotherwise specifically in the specification, a bicycloalkyl isoptionally substituted.

“Carboxyalkyl” refers to a moiety of the formula —R_(b)—R_(c) whereR_(b) is an alkylene chain as defined herein and R_(c) is a carboxygroup as defined herein. Unless stated otherwise specifically in thespecification, carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b)is an alkylene chain as defined herein and R_(c) is a cyano group asdefined herein. Unless stated otherwise specifically in thespecification, a cyanoalkyl group is optionally substituted.

“Carbocycle” or “carbocyclic ring” refers to a saturated or unsaturated,non-aromatic, monocyclic or polycyclic hydrocarbon moiety, which mayinclude fused or bridged ring systems, having from three to fifteencarbon atoms, preferably having from three to ten carbon atoms,including cycloalkyls, cycloalkenyls, etc. “Cycloalkyl” refers to asaturated, non-aromatic, monocyclic or polycyclic hydrocarbon moiety,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms.Monocyclic cycloalkyl moieties include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl moieties include, forexample, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A “cycloalkenyl” is acycloalkyl comprising one or more carbon-carbon double bonds within thering, such as cyclopentenyl and cyclohexenyl. Unless otherwise statedspecifically in the specification, a cycloalkyl group is optionallysubstituted.

“Cycloalkylalkyl” refers to a moiety of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined herein and R_(d) is a cycloalkylmoiety as defined herein. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group is optionally substituted.

“Cycloalkylalkylamino” refers to a cycloalkylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl and where the cycloalkylalkyl moiety is attached viaa carbon atom to nitrogen, wherein the nitrogen functions as a linker toattach the moiety to the remainder of the molecule. Unless statedotherwise specifically in the specification, a cycloalkylalkylamino isoptionally substituted.

“Cycloalkylalkyloxy” refers to a —O-cycloalkylalkyl moiety, where thecycloalkylalkyl moiety is attached via a carbon atom to oxygen, whereinthe oxygen functions as a linker to attach the moiety to the remainderof the molecule. Unless stated otherwise specifically in thespecification, a cycloalkylalkyloxy is optionally substituted.

“Cycloalkylamino” refers to a —NR_(a)-cycloalkyl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, acycloalkylamino is optionally substituted.

“Cycloalkyloxy” refers to an —O-cycloalkyl moiety. Unless statedotherwise specifically in the specification, a cycloalkyloxy isoptionally substituted.

“Halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an alkyl group, as defined herein, that issubstituted by one or more halo atoms, as defined herein, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CHFCF₃, —CHFCHF₂, —CHFCH₂F, —CHFCH₃, —CF₂CF₃,—CF₂CHF₂, —CF₂CH₂F, —CF₂CH₃, —CH₂CF₂CH₃, —CH₂CHFCH₃,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless statedotherwise specifically in the specification, a haloalkyl group isoptionally substituted.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude any element other than carbon or hydrogen. Preferred heteroatomsare oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

“Heteroalkyl,” by itself or in combination with another term, means,unless otherwise stated, a straight or branched chain; monocyclic orpolycyclic moiety, which may include fused or bridged ring systems; orany combination thereof, comprising at least one carbon atom and atleast one heteroatom, such as O, N, P, Si and S, wherein one or moreheteroatoms may be oxidized. Heteroatom(s) may be positioned within thealkyl moiety, e.g., —CH₂—O—CH₂—; at a point of connectivity with theremainder of the molecule, e.g., —SO₂CH(CH₃)CH₂—; or a combinationthereof, e.g., —NH₂CH₂CH₂SO₂CH₂—. Unless stated otherwise specificallyin the specification, a heteroalkyl group is optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system moiety comprisingone to thirteen carbon atoms; one to six heteroatoms such as nitrogen,oxygen, and sulfur; and one or multiple rings wherein at least one ringis aromatic. For purposes of this invention, the heteroaryl group may bea monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which mayinclude fused or bridged ring systems and one or more heteroatoms may beoxidized. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group is optionallysubstituted.

“Heteroarylalkyl” refers to a moiety of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined herein and R_(f) is a heteroarylgroup as defined herein. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group is optionally substituted.

“Heteroarylalkylamino” refers to a heteroarylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl. Unless stated otherwise specifically in thespecification, an heteroarylalkylamino is optionally substituted.

“Heteroarylalkyloxy” refers to an heteroarylalkyl-O— moiety. Unlessstated otherwise specifically in the specification, a heteroarylalkyloxyis optionally substituted.

“Heteroarylamino” refers to a —NR_(a)-heteroaryl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, aheteroarylamino is optionally substituted.

“Heteroaryloxy” refers to an —O-heteroaryl moiety. Unless statedotherwise specifically in the specification, an heteroaryloxy isoptionally substituted.

“Heterobicycloalkyl” refers to a bicycloalkyl structure in which atleast one carbon ring atom is replaced with a heteroatom such as oxygen,nitrogen, and sulfur. Unless stated otherwise specifically in thespecification, a heterobicycloalkyl is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a 3- to 18-memberednon-aromatic ring which consists of two to twelve carbon atoms and fromone to six heteroatoms such as nitrogen, oxygen, and sulfur. Unlessstated otherwise specifically in the specification, the heterocyclylgroup is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system,which may include fused or bridged ring systems; the heteroatoms may beoptionally oxidized; and the heterocyclyl may be unsaturated orsaturated. Examples of such heterocyclyl moieties include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group is optionally substituted.

“Heterocyclylalkyl” or “heterocycloalkyl” refers to a moiety of theformula —R_(b)R_(e) where R_(b) is an alkylene chain as defined hereinand R_(e) is a heterocyclyl moiety as defined herein, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl isoptionally attached to the alkyl moiety at the nitrogen atom. Unlessstated otherwise specifically in the specification, a heterocyclylalkylgroup is optionally substituted.

“Heterocyclylalkylamino” refers to a heterocyclylalkyl-NR_(a)— moiety,where R_(a) is H or alkyl and where the heterocyclylalkyl moiety isattached via a carbon atom to nitrogen, wherein the nitrogen functionsas a linker to attach the moiety to the remainder of the molecule.Unless stated otherwise specifically in the specification, aheterocyclylalkylamino is optionally substituted.

“Heterocyclylalkyloxy” refers to a —O-heterocycloalkyl moiety, where theheterocyclylalkyl moiety is attached via a carbon atom to oxygen,wherein the oxygen functions as a linker to attach the moiety to theremainder of the molecule. Unless stated otherwise specifically in thespecification, a heterocyclylalkyloxy is optionally substituted.

“Heterocyclylamino” refers to a —NR_(a)-heterocyclyl moiety, where R_(a)is H or alkyl and where the heterocyclyl moiety is attached via a carbonatom to nitrogen, wherein the nitrogen functions as a linker to attachthe moiety to the remainder of the molecule. Unless stated otherwisespecifically in the specification, a heterocyclylamino is optionallysubstituted.

“Heterocyclyloxy” refers to an —O-heterocyclyl moiety, where theheterocyclyl moiety is attached via a carbon atom to oxygen, wherein theoxygen functions as a linker to attach the moiety to the remainder ofthe molecule. Unless stated otherwise specifically in the specification,a heterocyclyloxy is optionally substituted.

“Hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl group comprising atleast one hydroxyl substituent. The —OH substituent may be on a primary,secondary, or tertiary carbon. Unless stated otherwise specifically inthe specification, a hydroxylalkyl group is optionally substituted.

“N-heteroaryl” refers to a heteroaryl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heteroaryl moiety to the rest of the molecule is through a nitrogenatom in the heteroaryl ring. Unless stated otherwise specifically in thespecification, an N-heteroaryl group is optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl moiety to the rest of the molecule is through anitrogen atom in the heterocyclyl ring. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group is optionallysubstituted.

“Thioalkyl” refers to a moiety of the formula —SR_(a) where R_(a) is analkyl moiety as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup is optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking two groups in a molecule, which may besaturated or unsaturated (i.e., contains one or more double and/ortriple bonds), and have from one to twelve carbon atoms, preferably oneto eight carbon atoms (C₁-C₈ alkylene) or one to six carbon atoms (C₁-C₆alkylene), e.g., methylene, ethylene, propylene, n-butylene, ethenylene,propenylene, n-butenylene, propynylene, n-butynylene, and the like. Thealkylene chain is attached to the rest of the molecule through a singleor double bond. The points of attachment of the alkylene chain to therest of the molecule may be through one carbon, e.g., methylene, or anytwo carbons within the chain, e.g., —CH₂CH(CH₃)CH₂CH₂—. Unless statedotherwise specifically in the specification, an alkylene chain isoptionally substituted.

“Alkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—, whereR_(a) is an alkylene chain as defined herein. Unless stated otherwisespecifically in the specification, an alkylenecarbonyl is optionallysubstituted.

“Alkenylene” is an unsaturated alkylene, as defined herein, whichcomprises one or more carbon-carbon double bonds. Unless statedotherwise specifically in the specification, an alkenylene is optionallysubstituted.

“Alkenylenecarbonyl” refers to an unsaturated alkylenecarbonyl, asdefined herein, which comprises one or more carbon-carbon double bonds.Unless stated otherwise specifically in the specification, analkenylenecarbonyl is optionally substituted.

“Arylene” refers to a divalent aryl group which links one part of themolecule to another part of the molecule. Unless stated specificallyotherwise, an arylene is optionally substituted.

“Heteroalkylene” refers to an alkylene group comprising at least oneheteroatom (e.g., N, O or S). In some embodiments, the heteroatom iswithin the alkylene chain (i.e., the heteroalkylene comprises at leastone carbon-heteroatom-carbon bond). In other embodiments, the heteroatomis at a terminus of the alkylene and joins the alkylene to the remainderof the molecule (e.g., M1-H-A-M2, where M1 and M2 are portions of amolecule, H is a heteroatom and A is an alkylene). A heteroalkylene mayhave both internal and terminal heteroatoms, e.g., —OCH₂CH₂OCH₂CH₂O—.Unless stated otherwise specifically in the specification, aheteroalkylene is optionally substituted.

“Heteroalkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,where R_(a) is a heteroalkylene chain as defined herein. Unless statedotherwise specifically in the specification, a heteroalkylenecarbonyl isoptionally substituted.

“Heteroarylene” refers to a divalent heteroaryl group which links onepart of the molecule to another part of the molecule. Unless statedspecifically otherwise, a heteroarylene is optionally substituted.

“Heteroarylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,wherein R_(a) is a heteroarylene as defined herein. Unless statedspecifically otherwise, a heteroarylenecarbonyl is optionallysubstituted.

“Heterocyclylalkylene” refers to a divalent heterocyclyl group whichlinks one part of the molecule to another part of the molecule. Unlessstated specifically otherwise, a heterocycloalkylene is optionallysubstituted.

“Heterocyclylalkylenecarbonyl” refers to a moiety of the formula—C(═O)R_(a)—, wherein R_(a) is a heterocycloalkylene as defined herein.Unless stated specifically otherwise, a heterocycloalkylenecarbonyl isoptionally substituted.

The term “substituted” used herein refers to replacement of at least onehydrogen atom with any of the above groups (e.g., amino, carboxy,hydroxyl, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl,amide, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino,aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy,cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom,heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino,heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino,heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl,N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl,alkenylene, alkenylenecarbonyl, arylene, heteroalkylene,heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl,heterocyclylalkylene, and/or heterocyclylalkylenecarbonyl), wherein theat least one hydrogen atom is replaced by a bond to a non-hydrogen atomsuch as, but not limited to: a halogen atom such as F, Cl, Br, and I; anoxygen atom in groups such as hydroxyl groups, alkoxy groups, and estergroups; a sulfur atom in groups such as thiol groups, thioalkyl groups,sulfone groups such as alkyl sulfone groups, sulfonyl groups such assulfonamide groups and sulfonylalkyl groups such as sulfonylmethane, andsulfoxide groups such as alkyl sulfoxide groups; a nitrogen atom ingroups such as amino, amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, imides, andenamines; a silicon atom in groups such as trialkylsilyl groups,dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilylgroups; a phosphorus atom in groups such as dialkylphosphine oxidegroups; and other heteroatoms in various other groups. “Substituted”also means any of the above groups in which one or more hydrogen atomsare replaced by a higher-order bond (e.g., a double- or triple-bond) toa carbon atom or a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. “Substituted” includes any of the above groupsin which one or more hydrogen atoms are replaced with —NR_(g)R_(h),—NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), —SO₂NR_(g)R_(h),—C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), or—CH₂SO₂NR_(g)R_(h), where R_(g) and Rh are independently hydrogen,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an amino, carbonyl, carboxy,cyano, hydroxyl, imino, nitro, oxo, thioxo, acyl, alkyl, alkoxy,alkylamino, alkylaminoalkyl, amide, aminoalkyl, aminocarbonyl, aryl,aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl,carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino,cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl,heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy,heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy,heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl,N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene,alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl,heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene,heterocyclylalkylenecarbonyl, trimethylsilanyl, dialkylphosphine oxide,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO(R^(a))₂, or—PO(OR^(a))₂ group, where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl group. In addition,each of the foregoing substituents is optionally substituted with one ormore of the above substituents. The term “optionally substituted”, asused herein, means that the referenced group (e.g., alkyl, cycloalkyl,etc.) may or may not be substituted with one or more additionalgroup(s).

As used herein, the term “absent” when used in reference to functionalgroup or substituent, particularly in reference to the chemicalstructure of a compound, means that the particular functional group orsubstituent is not present in the compound being described. When used inreference to a substituent (e.g., a pendant group, not a linking group),the absence of the substituent typically means that the bond to thesubstituent is absent and that absense of the bond is compensated forwith a H atom. When used in reference to a position within a chain orring (e.g., a linking group, not a pendant group), the absence of theposition typically means that the two positions otherwise connected bythe absent position are either (1) directly connected by a covalentbond, or (2) not connected, as will either be apparent from thestructure or explicitly indicated.

As used herein, the terms “ring system” and “multiring system” refer toa chemical structure or moiety comprising two or more rings that shareat least one bond (and two or more atomic positions). For example, amultiring system comprising a cyclohexane and cyclopentane is:

If an aryl or heteroaryl ring is included in a multiring system, thearomaticity of the ring is maintained, unless described otherwise, forexample, a multiring system comprising a benzene and cyclohexane is:

DETAILED DESCRIPTION

Provided herein are small molecule inhibitors of NSD1, NSD2 and/or NSD3activity and methods of use thereof for the treatment of disease,including leukemia, solid cancers and other diseases dependent on theactivity of NSD1, NSD2 and/or NSD3.

Experiments were conducted during development of embodiments herein todevelop small molecule inhibitors that block the catalytic activity ofNSD1 SET domain, and/or bind to NSD1 SET domain and facilitate itsdegradation. Such compounds will be effective in, for example,eradicating the Nup98-NSD1 positive leukemic cells, representing aneffective therapeutic approach for this aggressive leukemia.

Crystallographic studies of NSD1 and exemplary compounds describedherein have defined a small molecule binding site within the SET domainof NSD1. Binding of a small molecule to that binding site blocks thecatalytic activity of NSD1. The crystallographic studies reveal that aclass of benzothiazole compounds, such as those defined by Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV) and/or the exemplarycompounds of Table 2, are exceptional well-suited for binding to NSD1.The crystallographic studies also demonstrate several structuralconstrains placed on the small molecules by the architecture of thepocket within NSD1

For example, the R⁴ substituent binds to an internal small pocket withinthe protein. As a result of the size constrains imposed by this pocket,only small substituents are accommodated by the pocket. Therefore, incertain embodiments, R⁴ substituents (and R^(4a) and R^(4b)substituents) are small enough to bind within the internal pocket atthis position. For example, in some embodiments, R⁴ substituents (andR^(4a) and R^(4b) substituents) are of a length of 10 Å or less (e.g.,10 Å, 9 Å, 8 Å, 7 Å, 6 Å, 5 Å, 4 Å, 3 Å, 2 Å, or less or rangestherebetween (e.g., 2-5 Å), etc.) or a mass of 50 amu or less (e.g., 50amu, 45 amu, 40 amu, 35 amu, 30 amu, 25 amu, 20 amu, 15 amu, or less, orranges therebetween (e.g., 15-35 amu), etc.).

Another example of a structural constrain placed on small moleculebinders of NSD1 is at the R⁷ substituent. This region of the smallmolecule binding pocket is highly constrained. Therefore, in someembodiments, R⁷ substituents (and R^(7a) and R^(7b) substituents) arelimited to H or D. In other embodiments, R⁷ substituents (and R^(7a) andR^(7b) substituents) are of a length of 5 Å or less (e.g., 5 Å, 4 Å, 3Å, 2 Å, or less or ranges therebetween (e.g., 2-5 Å), etc.) or a mass of30 amu or less (e.g., 30 amu, 25 amu, 20 amu, 15 amu, or less, or rangestherebetween).

In contrast to the R⁴ and R⁷, the size and shape of substituents at theR², R⁵, and R⁶ positions are relatively unconstrained by thearchitecture of the pocket. Therefore, as is described in detail herein,a wide variety of substituents may be present at these positions forcompounds within the scope of the invention.

In some embodiments, provided herein are small molecule inhibitorsdirectly targeting the SET domain of NSD1 and blocking its catalyticactivity. In experiments conducted during development of embodimentsherein, small molecule inhibitors of NSD1 demonstratedanti-proliferative effect in Nup98-NSD1 leukemia cells and downregulateexpression of Hoxa9 target gene.

In some embodiments, the compounds described herein find use in thetreatment or prevention of disease (e.g., cancer (e.g., leukemia, breastcancer, ovarian cancer, melanoma, prostate cancer, osteosarcoma, lungcancer, thyroid cancer, or metastasis thereof), muscular dystrophy,liver fibrosis, etc.) and/or the alleviation of symptoms associatedtherewith. In some embodiments, provided herein are pharmaceuticalcompositions comprising a compound described and/or within the scopeherein. In some embodiments, pharmaceutical compositions comprising acompound described and/or within the scope herein are administered to asubject to treat a disease of condition (e.g., cancer (e.g., leukemia,breast cancer, ovarian cancer, melanoma, prostate cancer, osteosarcoma,lung cancer, thyroid cancer, or metastasis thereof), muscular dystrophy,liver fibrosis, etc.).

In some embodiments, provided herein are compounds comprising astructure of Formula (I):

or a salt thereof;

-   wherein X, R², R^(4,) R⁵, R⁶, and R⁷ are independently selected from    any suitable substituents (e.g., pendant groups) described herein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIa):

or a salt thereof;

wherein X, R², R^(4,) R⁵, L¹, A, L², Y, and R⁷ are independentlyselected from any suitable substituents (e.g., pendant groups) describedherein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIb):

or a salt thereof;

wherein X, R², R^(4,) R⁵, Z, A, L, Y, and R⁷ are independently selectedfrom any suitable substituents (e.g., pendant groups) described herein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIc):

or a salt thereof;

-   wherein X, R², R^(4,) R⁵, Z, L, Y, R⁷, and R⁸ are independently    selected from any suitable substituents (e.g., pendant groups)    described herein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IId):

or a salt thereof;

wherein X, R², R^(4,) R⁵, Z, A, L, E, Y, and R⁷ are independentlyselected from any suitable substituents (e.g., pendant groups) describedherein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IIe):

or a salt thereof;

wherein X, R², R^(4,) R⁵, Z, L, A, Y, R⁷, and R⁸ are independentlyselected from any suitable substituents (e.g., pendant groups) describedherein.

In some embodiments, provided herein are compounds comprising astructure of Formula (III):

or a salt thereof;

wherein R², R^(4,) R⁵, R⁶, and R⁷ are independently selected from anysuitable substituents (e.g., pendant groups) described herein.

In some embodiments, provided herein are compounds comprising astructure of Formula (IV):

or a salt thereof;

wherein G, X, R^(2a), R^(4a), R^(5a), R^(6a), R^(7a), R^(2b), R^(4b),R^(5b), R^(6b), and R^(7b) are independently selected from any suitablesubstituents (e.g., pendant groups) described herein.

In some embodiments, when rings are present in the compounds describedherein, other than the core benzothiazole ring (e.g., A-ring, E-ring,any Q ring, or any other non-aromatic carbocycle, non-aromaticheterocycle, aryl, heteroaryl, or multi-ring system present within oneor more of the substituent groups), rings are selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, anoptionally substituted 5-membered cycloalkyl, an optionally substituted6-membered cycloalkyl, an optionally substituted 5-membered carbocycle,an optionally substituted 6-membered carbocycle, an optionallysubstituted 5-membered non-aromatic heterocycle, or an optionallysubstituted 6-membered non-aromatic heterocycle. In some embodiments, aring structure (e.g., A-ring, E-ring, any Q ring, or any othernon-aromatic carbocycle, non-aromatic heterocycle, aryl, heteroaryl, ormulti-ring system present within one or more of the substituent groups)is selected from the ring structures listed in Table 1. The rings may belinked to the benzothiazole ring or a portion of a substituent at anysuitable position of the ring, and may optionally be furthersubstituted.

As noted above, the any substituents substituents present in a compoundof any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV) may be of any suitable chemical functional group, such as:

-   -   single atoms: H, Cl, Br, F, or I;    -   alkyl groups: methyl, ethyl, propyl, butyl, pentyl, hexyl, or        any suitable straight chain or branched C¹-C¹⁰ alkyl group;    -   alkenyl: ethenyl, propenyl, butenyl, pentenyl, hexenyl, or any        suitable C¹-C¹⁰ alkenyl group;    -   alkynyl: ethynyl, propynyl, butynyl, pentynyl, hexynyl, or any        suitable C¹-C¹⁰ alkenyl group;    -   cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or        any suitable C³-C⁷ cycloalkyl group; optionally further        substituted;    -   cycloalkenyl: cyclopropene, cyclobutene, cyclopentene,        cyclohexene, cycloheptene, 1,3-cyclohexadiene,        1,4-cyclohexadiene, 1,5-cyclooctadiene; optionally further        substituted;    -   aryl or heteroaryl: furan, benzofuran, isobenzofuran, pyrrole,        indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene,        imidazole, benzimidazole, purine, pyrazole, indazole, oxazole,        benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,        benzene, napthalene, pyridine, quinolone, isoquinoline,        pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine,        cinnoline, phthalazine, triazine (e.g., 1,2,3-triazine;        1,2,4-triazine; 1,3,5 triazine), thiadiazole, etc.; optionally        further substituted;    -   non-aromatic heterocyclic rings: aziridine, thiirane        (episulfides), oxirane (ethylene oxide, epoxides), oxaziridine,        dioxirane, azetidine, oxetan, thietane, diazetidine, dioxetane,        dithietane, pyrrolidine, tetrahydrofuran, thiolane,        imidazolidine, pyrazolidine, oxazolidine, isoxazolidine,        thiazolidine, isothiazolidine, dioxolane, dithiolane,        piperidine, oxane, thiane, pepierazine, morpholine,        thiomorpholine, dioxane, dithiane, trioxane, thithiane, azepane,        oxepane, thiepane, homopiperazine, azocane, tetrahydropyran,        etc.;    -   haloalkanes: halomethane (e.g., chloromethane, bromomethane,        fluoromethane, iodomethane), di-and trihalomethane (e.g.,        trichloromethane, tribromomethane, trifluoromethane,        triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane,        1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane,        1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and        any other suitable combinations of alkanes (or substituted        alkanes) and halogens (e.g., Cl, Br, F, I, etc.), and branched        haloalkanes;    -   alcohols: OH, methanol, ethanol, propanol, butanol, pentanol,        hexanol, cyclic alcohols (e.g., cyclohexanol), aromatic alcohols        (e.g., phenol), or any other suitable combination of an OH        moiety with a second moiety, branched alcohols;    -   ketones: methyl methyl ketone (acetone), methyl ethyl ketone        (butanone), propyl ethyl ketone (pentanone), or any other        suitable combination of alkyl chains with ═O;    -   aldehydes: methanal, ethanal, propanal, butanal, pentanal,        hexanal, or any other suitable combination of alkyl chain with        ═O;    -   carboxylates: methanoate, ethanoate, propanote, butanoate,        pentanoate, hexanoate, or any other suitable combination of        alkyl chain with OO⁻;    -   carboxylic acids: methanoic acid, ethanoic acid, propanoic acid,        butanoic acid, pentanoic acid, hexanoic acid, or any other        suitable combination of alkyl chain with OOH;    -   ethers: methoxy, ethoxy, methylmethoxy, ethylmethoxy, or any        other suitable combination of alkyl chains surrounding an O;    -   amides: methanamide (CONH₂), ethanamide (CH₂CONH₂), propanamide        ((CH₂)₂CONH₂), alkan^(n)amide ((CH₂)_(n)CONH₂), n-methyl        alkan^(n)amide ((CH₂)_(n)CONHCH₃), c-methyl alkan^(n)amide        ((CH₂)_(n)NHCOCH₃), n-alkyl alkan^(n)amide        ((CH₂)_(n)CONH(CH₂)_(m)CH₃), c-methyl alkan^(n)amide        ((CH₂)_(n)NHCO(CH₂)_(m)CH₃), etc.;    -   primary amines: NH₂, methylamine, ethylamine, cyclopropylamine,        etc.; secondary amines aminomethyl (NHCH₃), aminoethyl        (NHCH₂CH₃), methyl-aminomethyl (CH₂NHCH₃; aka        methylamine-methane), alkyl^(n)-aminomethane ((CH₂)_(n)NHCH₃),        etc.;    -   tertiary amines dimethylamine (N(CH₃)₂), dimethylamine        (N(CH₃)₂), methyl-ethyl-amine (NCH₃CH₂CH₃), methane-diethylamine        (CH₂N(CH₂CH₃)₂; aka methylamine-diethane), etc.;    -   azides: methyl azide (CH₂NNN), ethyl azide ((CH₂)₂NNN),        alkyl^(n) azide ((CH₂)_(n)NNN), etc.;    -   cyanates: methyl cyanate (CH₂OCN), ethyl cyanate ((CH₂)₂OCN),        cyanate ((CH₂)_(n)OCN), etc.;    -   Cyanos: cyano (—CN), methyl carbonitrile (CH₂CN), ethyl        carbonitrile ((CH₂)₂CN), alkyl^(n) carbonitrile ((CH₂)_(n)CN),        etc.    -   thiols: methanethiol (CH₂SH), ethanethiol ((CH₂)₂SH),        alkan^(n)ethiol ((CH₂)_(n)SH), etc.    -   sulfides: dimethyl sulfide (CH₂SCH₃), methyl-ethyl sulfide        (CH₂SCH₂CH₃), alkyl^(n)-alkyl^(m) sulfide        ((CH₂)_(n)S(CH₂)_(m-1)CH₃), etc.;    -   sulfoxides: dimethyl sulfoxide (CH₂SOCH₃), methyl-ethyl        sulfoxide (CH₂SOCH₂CH₃), alkyl^(n)-alkyl^(m) sulfoxide        ((CH₂)_(n)SO(CH₂)_(m-1)CH₃), etc.;    -   sulfone: dimethyl sulfone (CH₂SO₂CH₃; aka        methyl-sulfone-methyl), methyl-ethyl sulfone (CH₂SO₂CH₂CH₃; aka        methyl-sulfone-ethyl), alkyl^(n)-alkyl^(m) sulfone ((CH₂)_(n)SO₂        (CH₂)_(m-1)CH₃; aka alkyl^(n)-sulfone-alkyl^(m)), R^(x)SO₂R^(y)        (wherein Rx and Ry are independently selected from any of the        moieties provided in this list or combinations thereof), etc.;    -   sulfuonamides: SO₂NH₂, methyl sulfonamide (CH₂SO₂NH₂), ethyl        sulfonamide ((CH₂)₂SO₂NH₂), alkyl^(n) sulfonamide        ((CH₂)_(n)SO₂NH₂), methyl methylsulfonamide (CH₂SO₂NHCH₃),        alkyl^(n) alkyl^(m)sulfonamide ((CH₂)_(n)SO₂NH(CH₂)_(m)CH₃,        etc.;    -   sulfinic acids: SO₂H, methyl sulfinic acid (CH₂SO₂H), ethyl        sulfinic acid ((CH₂)₂SO₂H), alkyl^(n) sulfinic acid        ((CH₂)_(n)SO₂H), etc.;    -   thiocyanate: SCN, methyl thiocyanate (CH₂SCN), ethyl thiocyanate        ((CH₂)₂SCN), alkyl^(n) thiocyanate ((CH₂)nSCN), etc.;    -   phosphates: OP(═O)(OH)₂, methyl phosphate (CH₂OP(═O)(OH)₂),        ethyl phosphate ((CH₂)₂OP(═O)(OH)₂), alkyl^(n) phosphate        ((CH₂)_(n)OP(═O)(OH)₂), etc.;        and suitable combinations thereof. For example, in some        embodiments, R², R⁴ (considering restrictions placed on this        substituent by the NSD1 pocket), R⁵, R⁶, R⁷, R⁸ (considering        restrictions placed on this substituent by the NSD1 pocket), and        R^(A1-5) substituents (when present) are independently selected        from: H, alkyl group (e.g., straight-chain alkyl (e.g., methyl,        ethyl, propyl, butyl, pentyl, hexyl, etc.), branched alkyl group        (e.g., iso-propyl, 2-methyl-hexyl, 3-methyl,2-propyl-octyl,        etc.), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched cyclic        alkyl (e.g., methylcyclohexyl, ethylcyclobutyl,        propylcyclohexyl, etc.)), a substituted alkyl group (e.g.,        halogen-substituted alkyl group (e.g., trihalobutane (e.g.        trifluorobutane), dihalobutane (e.g. difluorobutane),        monohalobutane (e.g. monofluorobutane), trihalopropane (e.g.        trifluoropropane), dihalopropane (e.g. difluoropropane),        monohalopropane (monofluoropropane), trihaloethane (e.g.,        trifluoroethane), dihaloethane (e.g. difluroethane), haloethane        (e.g. fluoroethane), halomethane (e.g., fluoromethane),        dihalomethane (e.g., difluoromethane), trihalomethane (e.g.,        trifluoromethane), an alkyl group substituted by halogens at        multiple carbons (e.g., 3-fluoro, 4-trifluoroisobutane,        2-difluoro, 3-fluoropropane, etc.), etc.), alkene (e.g., CH═CH₂,        CH₂CH═CH₂, CH═CHCH₃, etc.), alkyne (e.g., C≡CH, C≡CCH₃, CH₂C≡CH,        etc.), alkoxy group (e.g., hydroxyl (e.g., (CH₂)₀₋₆OH, ether        ((CH₂)₀₋₆O(CH2)₀₋₆)), halogen substituted alkoxy (4-trifluoro,        3-isobutanol, 3-difluoro, 2-propanol, etc.), amine (e.g., NH₂),        alkylamine (e.g., primary amine (e.g., ethylamine,        iso-butylamine, n-propylamine, sec-butylamine, iso-propylamine,        iso-amylamine, methylamine, dimethylamine, n-amylamine, etc.),        secondary amines (e.g., dimethylamine, methylethanolamine,        diphenylamine, etc.), tertiary amine (e.g., trimethylamine,        triphenylamine, etc.), thioalkyl (e.g., thiol (e.g.,        (CH₂)₀₋₆—SH), thioether (e.g., (CH₂)₀₋₆—S—(CH₂)₀₋₆), etc.),        substituted ethers and thioethers, combinations thereof, etc.),        a substituted cycloalkyl group (e.g., halogen-substituted        cycloalkyl group, cycloalkoxy group, cycloalkylamine, etc.), a        halogen substituted alkyl amine (e.g., trifluromethylamine,        trifluoroethylamine, trifluorobutylamine, etc.), a halogen        (e.g., F, Cl, Br, I, and At), a ketone, an amide, an alkylamide,        a cyano group, methyl carbonitrile (e.g. CH₂CN), —SO₂CH₃ group,        —SO₂NH₂ group, sulfonyl group (e.g., methyl sulfonyl, ethyl        sulfonyl, propyl sulfonyl), substituted alkyl sulfonyl (e.g.,        trifluoroethyl sulfonyl), etc.), sulfonamine (e.g.,        (CH₂)₀₋₆SO₂NH₂, (CH₂)₀₋₆NHSO₂, (CH₂)₀₋₆NHSO₂(CH₂)₀₋₆,        (CH₂)₀₋₆SO₂NH(CH₂)₀₋₆, etc.), dialkylphosphine oxide (e.g.,        —PO(CH₃)₂), a carbocyclic ring (substituted or non-substituted),        a heterocyclic ring (substituted or non-substituted), an        aromatic ring, a substituted aromatic ring (e.g., branched        aromatic ring (e.g.,ethylbenzene, methyl benzene, etc.),        halobenzene (e.g., chlorobenzene, fluorobenzene, etc.)), a        carbocyclic (substituted or non-substituted), aryl carbocyclic        (substituted or non-substituted), heteroaryl (substituted (e.g.,        sulfonyl substituted, halo-substituted, etc.) or        non-substituted), an alkyl-linked carbocyclic ring (substituted        or non-substituted), an alkyl-linked heterocyclic ring        (substituted or non-substituted), an alkyl-linked aromatic ring        (substituted or non-substituted), an alkyl-linked substituted        aromatic ring, alkyl-linked halobenzene (e.g., chlorobenzene,        fluorobenzene, etc.)), an alkyl-linked carbocyclic (substituted        (e.g., halo substituted, trihalo-alkyl substituted, etc.) or        non-substituted), an alkyl-linked aryl carbocyclic (substituted        or non-substituted), an alkyl-linked heteroaryl (substituted or        non-substituted), an amine-linked carbocyclic ring (substituted        or non-substituted), an amine-linked heterocyclic ring        (substituted or non-substituted), an amine-linked aromatic        ring(substituted or non-substituted), an amine-linked        substituted aromatic ring, amine-linked halobenzene, an        amine-linked carbocyclic (substituted or non-substituted), an        amine-linked aryl carbocyclic (substituted or non-substituted),        an amine-linked heteroaryl (substituted or non-substituted), an        alkylamine-linked carbocyclic ring (substituted or        non-substituted), an alkylamine-linked heterocyclic ring        (substituted or non-substituted), an alkylamine-linked aromatic        ring(substituted or non-substituted), an alkylamine-linked        substituted aromatic ring, alkylamine-linked halobenzene, an        alkylamine-linked carbocyclic (substituted or non-substituted),        an alkylamine-linked aryl carbocyclic (substituted or        non-substituted), an alkylamine-linked heteroaryl (substituted        or non-substituted), an ether-linked carbocyclic ring        (substituted or non-substituted), an ether-linked heterocyclic        ring (substituted or non-substituted), an ether-linked aromatic        ring (substituted or non-substituted), an ether-linked        substituted aromatic ring, ether-linked halobenzene, an        ether-linked carbocyclic (substituted or non-substituted), an        ether-linked aryl carbocyclic (substituted or non-substituted),        an ether-linked heteroaryl (substituted or non-substituted), a        thioether-linked carbocyclic ring (substituted or        non-substituted), a thioether-linked heterocyclic ring        (substituted or non-substituted), a thioether-linked aromatic        ring (substituted or non-substituted), a thioether-linked        substituted aromatic ring, a thioether-linked halobenzene, a        thioether-linked carbocyclic (substituted or non-substituted), a        thioether-linked aryl carbocyclic (substituted or        non-substituted), a thioether-linked heteroaryl (substituted or        non-substituted), a sulfonyl-linked carbocyclic ring        (substituted or non-substituted), a sulfonyl-linked heterocyclic        ring (substituted or non-substituted), a sulfonyl-linked        aromatic ring (substituted or non-substituted), a        sulfonyl-linked substituted aromatic ring, a sulfonyl-linked        halobenzene, a sulfonyl-linked carbocyclic (substituted or        non-substituted), a sulfonyl-linked aryl carbocyclic        (substituted or non-substituted), a sulfonyl-linked heteroaryl        (substituted or non-substituted), a sulfonamide-linked        carbocyclic ring (substituted or non-substituted), a        sulfonamide-linked heterocyclic ring (substituted or        non-substituted), a sulfonamide-linked aromatic ring        (substituted or non-substituted), a sulfonamide-linked        substituted aromatic ring, a sulfonamide-linked halobenzene, a        sulfonamide-linked carbocyclic (substituted or non-substituted),        a sulfonamide-linked aryl carbocyclic (substituted or        non-substituted), a sulfonamide-linked heteroaryl (substituted        or non-substituted), an amide-linked carbocyclic ring        (substituted or non-substituted), an amide-linked heterocyclic        ring (substituted or non-substituted), an amide-linked aromatic        ring (substituted or non-substituted), an amide-linked        substituted aromatic ring, amide-linked halobenzene, an        amide-linked carbocyclic (substituted or non-substituted), an        amide-linked aryl carbocyclic (substituted or non-substituted),        an amide-linked heteroaryl (substituted (e.g., alkyl pyrrole,        pyrrole amine, pyrrole ether, etc.) or non-substituted (e.g.,        imidazole, indole), an alkylamide-linked carbocyclic ring        (substituted or non-substituted), an alkylamide-linked        heterocyclic ring (substituted or non-substituted), an        alkylamide-linked aromatic ring (substituted or        non-substituted), an alkylamide-linked substituted aromatic        ring, alkylamide-linked halobenzene, an alkylamide-linked        carbocyclic (substituted or non-substituted), an        alkylamide-linked aryl carbocyclic (substituted or        non-substituted), an alkylamide-linked heteroaryl (substituted        or non-substituted), a carbamide-linked carbocyclic ring        (substituted or non-substituted), a carbamide-linked        heterocyclic ring (substituted or non-substituted), a        carbamide-linked aromatic ring (substituted or non-substituted),        a carbamide-linked substituted aromatic ring, a carbamide-linked        halobenzene, a carbamide-linked carbocyclic (substituted or        non-substituted), a carbamide-linked aryl carbocyclic        (substituted or non-substituted), a carbamide-linked heteroaryl        (substituted or non-substituted), a bridged carbocyclic ring        (substituted or non-substituted), a bridged heterocyclic ring        (substituted or non-substituted), a bridged aromatic ring        (substituted or non-substituted), a bridged substituted aromatic        ring, a bridged halobenzene, a bridged carbocyclic (substituted        or non-substituted), a bridged aryl carbocyclic (substituted or        non-substituted), a bridged heteroaryl (substituted or        non-substituted), and/or combinations thereof.

In some embodiments, any of the R² and/or R⁵substituents, when presentin a compound of any one of Formulas (I), (IIa), (IIb), (IIc), (IId),(IIe), (III) or (IV) are of one of Formulas (a)-(q):

wherein one of J, Q¹, or J¹, when present, is linked to one of the D, G,A, E, or M rings;

wherein each J, J¹, J², J³, and J⁴, when present, are independentlyselected from the group consisting of: a covalent bond, H, alkyl₁₋₁₅,alkenyl₁₋₆, alkynyl₁₋₆, (CH₂)₀₋₆C(S)NH₂, (CH₂)₀₋₆C(O)NH₂, O, S, NH,(CH₂)₀₋₆C(O)NH(CH₂)₁₋₆, (CH₂)₀₋₆C(S)NH(CH₂)₁₋₆, (CH₂)₀₋₆O(CH₂)₁₋₆,(CH₂)₀₋₆OH, (CH₂)₀₋₆S(CH₂)₁₋₆, (CH₂)₀₋₆SH, (CH₂)₀₋₆NHC(O)(CH₂)₁₋₆,alkylsulfonyl, sulfonamide, alkylsulfonamide, (CH₂)₀₋₆NH(CH₂)₁₋₆,(CH₂)₀₋₆N(CH₂)₁₋₆(CH₂)₁₋₆ (See, e.g., Compound 80), (CH₂)₀₋₆NH₂,(CH₂)₀₋₆SO₂ (CH₂)₁₋₆, (CH₂)₀₋₆NHSO₂(CH₂)₁₋₆ (CH₂)₀₋₆SO₂ NH₂, halogen(e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH₂)₀₋₆ CH₂F,(CH₂)₀₋₃CHF(CH₂)₀₋₂CH₃, or similar with Br, Cl, or I), dihaloalkyl(e.g., (CH₂)₀₋₆ CF₂H, (CH₂)₀₋₃ CF₂(CH₂)₀₋₂CH₃, or similar with Br, Cl,or I), trihaloalkyl (e.g., (CH₂)₀₋₆ CF₃, or similar with Br, Cl, or I),alkyl with 1-3 halogens at two or more positions along its length,(CH₂)₁₋₄SP(Ph)₂═S, (CH₂)₀₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)_(1-5511,) (CH₂)₀₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆O(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆O(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆NH(CH₂)₁₋₅SH, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅OH,(CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅NH₂, (CH₂)₀₋₆S(CH₂)₁₋₆O(CH₂)₁₋₅SH,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅OH, (CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅NH₂,(CH₂)₀₋₆S(CH₂)₁₋₆S(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆NH(CH₂)₁₋₅SH,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅OH, (CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅NH₂,(CH₂)₀₋₆NH(CH₂)₁₋₆O(CH₂)₁₋₅SH, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅OH,(CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅NH₂, (CH₂)₀₋₆NH(CH₂)₁₋₆S(CH₂)₁₋₅SH,(CH₂)₀₋₃C(O)O(CH₂)₀₋₃, (CH₂)₀₋₃C(S)O(CH₂)₀₋₃, (CH₂)₀₋₃C(O)S(CH₂)₀₋₃,(CH₂)₀₋₃C(S)S(CH₂)₀₋₃, (CH₂)₀₋₃C(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃C(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)(CH₂)₀₋₃,(CH₂)₀₋₃OC(S)(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)NH(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)NH(CH₂)₀₋₃,(CH₂)₀₋₃NHC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(S)O(CH₂)₀₋₃,(CH₂)₀₋₃OC(O)O(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃SC(O)O(CH₂)₀₋₃,(CH₂)₀₋₃SC(S)O(CH₂)₀₋₃, (CH₂)₀₋₃NHC(O)S(CH₂)₀₋₃,(CH₂)₀₋₃NHC(S)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃OC(S)S(CH₂)₀₋₃,(CH₂)₀₋₃SC(O)S(CH₂)₀₋₃, (CH₂)₀₋₃SC(S)S(CH₂)₀₋₃, (CH₂O)₁₋₆, and trimethylmethane;

wherein each Q, Q¹, and Q², when present, is independently selected fromthe group consisting of: furan, benzofuran, isobenzofuran, pyrrole,indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene,imidazole, benzimidazole, purine, pyrazole, indazole, oxazole,benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,benzene, napthalene, pyridine, quinolone, isoquinoline, pyrazine,quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline,phthalazine, thalidomide, triazine (e.g., 1,2,3-triazine;1,2,4-triazine; 1,3,5 triazine), thiadiazole, aziridine, thiirane(episulfides), oxirane (ethylene oxide, epoxides), oxaziridine,dioxirane, azetidine, oxetan, thietane, diazetidine, dioxetane,dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine,pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,dioxolane, dithiolane, piperidine, oxane, thiane, pepierazine,morpholine, thiomorpholine, dioxane, dithiane, trioxane, thithiane,azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran,cyclobutene, cyclopentene, cyclohexene, cycloheptene,1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, any suitable C³-C⁷ cycloalkylgroup, and any of the ring structures depicted in Table 1;

wherein each Q, Q¹, and Q², when present, may display one or moreadditional J groups at any position on the Q ring;

wherein any alkyl or (CH₂)_(x-y) groups above may be straight orbranched;

wherein any alkyl or (CH₂)_(x-y) groups above may additionally compriseOH, ═O, NH₂, CN, dihaloalkyl (e.g., CF₂H), trihaloalkyl (e.g., CF₃), orhalogen (e.g., F) substituents at one or more carbons;

wherein the number of hydrogens on terminal positions of the groupsabove may be adjusted if the group is linked to an additional group(e.g., CH₃ adjusted to CH₂, OH adjusted to O, etc.) or if the group isterminal (e.g., CH₂ adjusted to CH₃, O adjusted to OH, etc.); and

wherein any of formulas (a)-(q) may additionally comprise a terminalfluorophore (e.g. fluorescein), solid surface, enzyme ligand (e.g.thalidomide or VHL ligand (e.g.,(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,etc.), or affinity tag (e.g. biotin).

A compound of any one of Formulas (I), (IIa), (IIb), (IIc), (IId),(IIe), (III) or (IV), may be selected from compounds listed in Table 2.Compounds of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV) that are not listed in Table 2 are also within the scope herein. Insome embodiments, compounds of Formulas (I), (IIa), (IIb), (IIc), (IId),(IIe), (III) or (IV) may comprise any of the substituents depicted inthe compounds of Table 2, in any suitable combinations.

TABLE 2 Exemplary compounds Mw [MH]⁺ calc. found Number Structure (Da)(Da)  1

222.08  2

208.07  3

180.04 181.0445  4

199.98 200.9892  5

227.94  6

226.06  7

194.05  8

180.04  9

227.94 228.9427  10

175.02 176.0271  11

180.04  12

118.01  13

121.06  14

226.06 227.0632  15

178.06 179.0633  16

166.02 167.0270  17

179.05  18

210.05  19

230.00  20

179.05 180.0591  21

257.95  22

243.93  23

190.06 191.0858  24

214.00  25

199.98  26

214.00  27

179.05  28

194.05  29

198.00  30

295.92  31

221.06  32

193.07  33

228.01 229.0225  34

214.00 215.0060  35

257.95 258.9545  36

222.99 223.9953  37

212.01  38

183.99  39

226.02 227.0338  40

240.04 241.0509  41

240.04 241.0503  42

210.05 211.0555  43

212.01 213.0184  44

303.93 304.9422  45

269.03  46

264.06  47

231.05  48

238.00  49

249.06  50

277.09  51

235.04  52

237.00  53

237.06  54

217.03  55

285.94  56

257.95  57

262.88  58

228.92  59

304.03 305.0417  60

294.01 295.0185  61

393.97 394.9756  62

480.05 [M + 2H]²⁺ 241.0337  63

557.97 558.9823  64

319.01 320.0144  65

165.02 166.0318  66

222.05 223.0536  67

244.93 245.9404  68

244.93 245.9406  69

207.98 208.9837  70

254.92 255.9253  71

190.02 191.0274  72

256.93 257.9416  73

270.97 271.9749  74

204.04 205.0437  75

220.03 221.0386  76

234.05 235.0532  77

280.07 281.0744  78

233.03 234.0332  79

206.05 207.0586  80

222.03 223.0336  81

294.08 295.0904  82

236.04 237.0494  83

249.06 250.0642  84

311.07 312.0802  85

233.06 234.0698  86

295.08 296.0853  87

266.05 267.0588  88

232.07 233.0742  89

313.07 314.0761  90

310.09 311.0965  91

364.10 365.1066  92

310.09 311.0962  93

302.03 303.0377  94

310.09 311.0962  95

363.07 364.0729  96

313.07 314.0761  97

329.04 330.0465  98

296.07 297.0804  99

329.04 330.0463 100

329.04 330.0467 101

313.07 314.0761 102

363.07 364.0733 103

363.07 364.0735 104

325.09 326.0963 105

309.09 310.1012 106

379.06 380.0678 107

299.08 300.0913 108

328.08 109

434.18 435.1854 110

428.13 429.1381 111

340.10 341.1066 112

434.18 435.1854 113

420.20 412.2062 114

420.20 115

414.15 116

414.15 415.1592 117

367.14 368.1436 118

367.14 368.1432 119

415.14 416.1432 120

280.07 281.45 121

256.03 257.36 122

242.02 243.35 123

256.03 257.45 124

254.05 255.40 125

254.05 255.40 126

280.00 281.30 127

341.09 342.45 128

241.03 242.40 129

237.00 238.40 130

387.03 389.30 131

286.97 289.90 132

327.00 329.90 133

288.04 134

184.01 135

222.00 136

205.07 137

191.05 138

203.05 139

206.05 140

234.08 141

220.07 142

195.01 143

307.96 144

193.07 145

220.07 146

235.04 147

194.01 148

207.05 208.0539 149

212.01 213.0146 150

206.05 207.0580 151

221.06 222.0695 152

235.08 236.0855 153

235.08 236.0852 154

297.09 298.1012 155

235.08 236.0853 156

315.08 316.0915 157

315.08 316.0914 158

342.08 343.0860 159

331.05 332.0620 160

331.05 332.0619 161

288.10 289.1117 162

313.09 314.0958 163

334.09 335.0965 164

390.15 391.1588 165

390.15 391.1589 166

257.95 258.9534 167

261.90 262.9039 168

285.07 286.0756 169

345.07 346.0777 170

300.05 301.0565 171

176.04 177.0482 172

165.04 166.0432 173

510.11 511.1219 174

536.16 537.1704 175

443.14 444.1487 176

443.14 444.1484 177

432.14 433.1444 178

430.15 431.1543 179

416.13 417.1379 180

512.16 513.1625 181

449.10 450.1063 182

492.22 493.2390 183

498.14 499.1474 184

553.18 540.1748 185

501.15 502.1583 186

513.15 514.1579 187

527.17 528.1736 188

448.10 449.1103 189

432.13 433.1331 190

457.16 458.1651 191

485.12 486.1268 192

499.13 500.1422 193

435.08 436.0898 194

432.14 433.1447 195

433.13 434.1396 196

457.09 458.0957 197

511.17 512.1752 198

471.10 472.1106 199

414.08 415.0894 200

438.08 439.0897 201

364.10 365.1068 202

366.12 367.1225 203

365.41 366.0909 204

365.41 366.0907 205

438.08 439.0898 206

429.13 207

447.08 210

388.10 211

349.09 350.0960 212

363.10 213

429.08 214

443.10 215

457.11 216

471.13 217

453.09 218

379.10 219

433.07 220

441.11 221

376.1 377.1068 222

416.10 417.1056 223

454.15 455.1543 224

454.15 455.1543 225

432.07 433.0800 226

432.07 433.0803 227

440.10 441.1053 228

428.10 429.1054 229

428.10 429.1053 230

448.05 449.0509 231

414.08 415.0897 232

440.10 441.1055 233

414.08 415.0896 234

446.10 447.1102 235

455.14 456.1493 236

466.11 467.1215 237

378.12 379.1228 238

457.12 458.1286 239

432.07 433.0806 240

428.10 429.1055 241

448.04 449.0505 242

457.12 458.1284 243

525.11 526.1158 244

781.22 782.2280 246

410.06 411.0683 247

490.11 491.1215 248

428.10 429.1056 249

442.11 443.1213 251

448.19 449.2014 252

420.16 421.1701 253

434.18 435.1858 254

408.16 409.1701 255

553.18 554.1892 256

468.14 469.1465 257

468.14 469.1463 258

410.06 411.0684 259

509.12 510.1274 261

424.08 425.0835 262

378.10 379.1021 263

360.10 361.1122 264

404.13 405.1381 265

390.12 391.1227 266

390.12 391.1226 267

394.07 395.0735 268

487.11 488.1213 269

374.12 375.1279 271

390.12 391.1227 272

394.09 395.0979 273

261.92 262.9286 274

421.07 275

400.10 276

361.09 277

380.13 278

392.11 279

410.10 281

455.13 456.1375 282

295.08 296.0852 283

310.08 311.0849 284

406.06 407.0675 285

415.07 416.0736 286

309.02 310.0316 287

415.07 416.0735 288

399.07 400.0789 289

335.07 336.0803 290

335.07 336.0803 291

449.03 450.0345 292

361.42 293

418.53 294

354.43 295

366.44 296

398.50 297

378.45 298

377.46 299

379.48 300

381.45 301

379.43 302

367.42 303

365.45 304

383.48 305

397.51 306

388.45 307

403.46 308

420.51 309

404.44 310

401.44 311

414.48In some embodiments, the substituents and functional groups of thecompounds of Table 2 may be recombined within the Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV) to yield compounds within thescope herein.

Exemplary compounds herein have been tested for binding to an NSD familyprotein. For example, compounds 25, 27, 39-43, 56, 60, 62, 63, 64, 66,74-82, 85, 93, 95, 105-107, 113, 116-119, 122-124, 126, 128, 131-133,147, 150, 155, 164, 165, 168, 169, 201, 202, 263, 264, 267, 268, 269,271, 273, 282-284, 286, 289, 290 exhibit an IC50 for an NSD familyprotein of between 20 μM and 200 μM. In some embodiments, compounds 22,36, 61, 71, 86, 89, 90-92, 94, 96-104, 108, 111, 112, 148, 149, 151-154,156, 160, 163, 173-199, 200, 203, 204, 205, 211, 221-262, 265-266, 272,281, 285, 287, 288, 291 exhibit an IC50 for an NSD family protein ofless than 20 μM.

The compounds described herein may in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or any combinationthereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

In some embodiments, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

Unless specified otherwise, divalent variables or groups describedherein may be attached in the orientation in which they are depicted orthey may be attached in the reverse orientation.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, etc. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds or salts described herein may beprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. In some embodiments, by virtueof knowledge of pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is determined, prodrugs of thecompound are designed. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985; Rooseboom et al., Pharmacological Reviews, 56:53-102,2004; Miller et al., J. Med. Chem. Vol. 46, no. 24, 5097-5116, 2003;Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reportsin Medicinal Chemistry, Vol. 41, 395-407, 2006).

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels,photoactivatable or chemiluminescent labels, affinity labels (e.g.biotin), degradation tags (e.g. thalidomide conjugates (e.g., compounds198, 199, etc.), VHL ligand conjugates (e.g., compound 302), etc.).

Compounds and salts described herein include isotopically-labeledcompounds. In general, isotopically-labeled compounds are identical tothose recited in the various formulae and structures presented herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber most common in nature. Examples of isotopes that can beincorporated into the present compounds include isotopes of hydrogen,carbon, nitrogen, oxygen, fluorine and chlorine, for example, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certainisotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Further,substitution with isotopes such as deuterium, i.e., ²H, can affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In some embodiments, compounds described herein, such as compounds ofany one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV) with any suitable substituents and functional groups disclosedherein, are in various forms, including but not limited to, amorphousforms, milled forms and nano-particulate forms. In addition, compoundsdescribed herein include crystalline forms, also known as polymorphs.Polymorphs include the different crystal packing arrangements of thesame elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, melting points, density, hardness,crystal shape, optical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Pharmaceutical Compositions

In certain embodiments, compounds or salts of any one of Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, are combined withone or more additional agents to form pharmaceutical compositions.Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound or salt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId),(IIe), (III) or (IV), with any suitable substituents and functionalgroups disclosed herein, with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds described herein are administered in apharmaceutical composition to a mammal having a disease, disorder, orcondition to be treated. In some embodiments, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds or saltsof any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein, can be used singly or in combination with one or moretherapeutic agents as components of mixtures (as in combinationtherapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of any one of Formulas (I), (IIa), (IIb),(IIc), (IId), (IIe), (III) or (IV), with any suitable substituents andfunctional groups disclosed herein, can be formulated into any suitabledosage form, including but not limited to, aqueous oral dispersions,liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fastmelt formulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, and capsules.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofany one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein, as an active ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipients with one or more of the compounds or salts ofany one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets, pills, or capsules. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form,multiparticulate dosage forms, pellets, granules, or an aerosol. Inother embodiments, the pharmaceutical formulation is in the form of apowder. In still other embodiments, the pharmaceutical formulation is inthe form of a tablet, including but not limited to, a fast-melt tablet.Additionally, pharmaceutical formulations of the compounds describedherein may be administered as a single capsule or in multiple capsuledosage form. In some embodiments, the pharmaceutical formulation isadministered in two, or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound orsalt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein, with one or more pharmaceutical excipients to form abulk blend composition. When referring to these bulk blend compositionsas homogeneous, it is meant that the particles of the compound or saltof any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein, are dispersed evenly throughout the composition so that thecomposition may be subdivided into equally effective unit dosage forms,such as tablets, pills, and capsules. The individual unit dosages mayalso include film coatings, which disintegrate upon oral ingestion orupon contact with diluent. These formulations can be manufactured byconventional pharmacological techniques.

The pharmaceutical solid dosage forms described herein can include acompound of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein, and one or more pharmaceutically acceptable additivessuch as a compatible carrier, binder, filling agent, suspending agent,flavoring agent, sweetening agent, disintegrating agent, dispersingagent, surfactant, lubricant, colorant, diluent, solubilizer, moisteningagent, plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other aspects, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of the compound described herein. In one embodiment, some orall of the particles of the compound described herein are coated. Inanother embodiment, some or all of the particles of the compounddescribed herein are microencapsulated. In still another embodiment, theparticles of the compound described herein are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound or salt of any one of Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, from a solid dosageform matrix as efficiently as possible, disintegrants are often used inthe formulation, especially when the dosage forms are compressed withbinder. Disintegrants help rupturing the dosage form matrix by swellingor capillary action when moisture is absorbed into the dosage form.Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 5400 to about 7000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating aids in patient compliance(e.g., Opadry® coatings or sugar coating). Film coatings includingOpadry® typically range from about 1% to about 3% of the tablet weight.In other embodiments, the compressed tablets include one or moreexcipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound or salt of any oneof Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), withany suitable substituents and functional groups disclosed herein, andone or more excipients are dry blended and compressed into a mass, suchas a tablet, having a hardness sufficient to provide a pharmaceuticalcomposition that substantially disintegrates within less than about 30minutes, less than about 35 minutes, less than about 40 minutes, lessthan about 45 minutes, less than about 50 minutes, less than about 55minutes, or less than about 60 minutes, after oral administration,thereby releasing the formulation into the gastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxidecan be used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound or salt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId),(IIe), (III) or (IV), with any suitable substituents and functionalgroups disclosed herein, are solid dispersions. Methods of producingsuch solid dispersions include, but are not limited to, for example,U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269,and U.S. patent publication no. 2004/0013734. In still otherembodiments, the formulations described herein are solid solutions.Solid solutions incorporate a substance together with the active agentand other excipients such that heating the mixture results indissolution of the drug and the resulting composition is then cooled toprovide a solid blend which can be further formulated or directly addedto a capsule or compressed into a tablet. Methods of producing suchsolid solutions include, but are not limited to, for example, U.S. Pat.Nos. 4,151,273, 5,281,420, and 6,083,518.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds or salt of any one of Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, and at least onedispersing agent or suspending agent for oral administration to asubject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the above-listed additives used in the aqueousdispersions or suspensions described herein, since a given additive isoften classified differently by different practitioners in the field, oris commonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in formulationsdescribed herein.

Potential excipients for intranasal formulations include, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulationssolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. The choice of suitable carriersis highly dependent upon the exact nature of the nasal dosage formdesired, e.g., solutions, suspensions, ointments, or gels. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal formulations that include compounds described herein may beadministered using a variety of formulations which include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described herein canfurther include a bioerodible (hydrolysable) polymeric carrier that alsoserves to adhere the dosage form to the buccal mucosa. The buccal dosageform is fabricated so as to erode gradually over a predetermined timeperiod, wherein the delivery of the compound is provided essentiallythroughout. Buccal drug delivery avoids the disadvantages encounteredwith oral drug administration, e.g., slow absorption, degradation of theactive agent by fluids present in the gastrointestinal tract and/orfirst-pass inactivation in the liver. With regard to the bioerodible(hydrolysable) polymeric carrier, virtually any such carrier can beused, so long as the desired drug release profile is not compromised,and the carrier is compatible with the compounds described herein, andany other components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal formulations described herein may be administered using avariety of devices including but not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound orsalt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein; (2) a penetration enhancer; and (3) an aqueousadjuvant. In addition, transdermal formulations can include additionalcomponents such as, but not limited to, gelling agents, creams andointment bases, and the like. In some embodiments, the transdermalformulation can further include a woven or non-woven backing material toenhance absorption and prevent the removal of the transdermalformulation from the skin. In other embodiments, the transdermalformulations described herein can maintain a saturated or supersaturatedstate to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Generally, an agent, such as a compound of any one of Formulas (I),(IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, is administered inan amount effective for amelioration of, or prevention of thedevelopment of symptoms of, the disease or disorder (i.e., atherapeutically effective amount). Thus, a therapeutically effectiveamount can be an amount that is capable of at least partially preventingor reversing a disease or disorder. The dose required to obtain aneffective amount may vary depending on the agent, formulation, diseaseor disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

In some embodiments, the compositions described herein are provided aspharmaceutical and/or therapeutic compositions. The pharmaceuticaland/or therapeutic compositions of the present invention can beadministered in a number of ways depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration can be topical (including ophthalmic and to mucousmembranes including vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal, intranasal, epidermal and transdermal), oralor parenteral. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Compositions and formulations for topical administrationcan include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalcarriers; aqueous, powder, or oily bases; thickeners; and the like canbe necessary or desirable. Compositions and formulations for oraladministration include powders or granules, suspensions or solutions inwater or non-aqueous media, capsules, sachets or tablets. Thickeners,flavoring agents, diluents, emulsifiers, dispersing aids or binders canbe desirable. Compositions and formulations for parenteral, intrathecalor intraventricular administration can include sterile aqueous solutionsthat can also contain buffers, diluents and other suitable additivessuch as, but not limited to, penetration enhancers, carrier compoundsand other pharmaceutically acceptable carriers or excipients.Pharmaceutical and/or therapeutic compositions of the present inventioninclude, but are not limited to, solutions, emulsions, and liposomecontaining formulations. These compositions can be generated from avariety of components that include, but are not limited to, preformedliquids, self-emulsifying solids and self-emulsifying semisolids.

The pharmaceutical and/or therapeutic formulations, which canconveniently be presented in unit dosage form, can be prepared accordingto conventional techniques well known in thepharmaceutical/nutriceutical industries. Such techniques include thestep of bringing into association the active ingredients with thepharmaceutical carrier(s) or excipient(s). In general the formulationsare prepared by uniformly and intimately bringing into association theactive ingredients with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product. The compositionsof the present invention can be formulated into any of many possibledosage forms such as, but not limited to, tablets, capsules, liquidsyrups, soft gels, suppositories, and enemas. The compositions of thepresent invention can also be formulated as suspensions in aqueous,non-aqueous, oil-based, or mixed media. Suspensions can further containsubstances that increase the viscosity of the suspension including, forexample, sodium carboxymethylcellulose, sorbitol and/or dextran. Thesuspension can also contain stabilizers. In one embodiment of thepresent invention the pharmaceutical compositions can be formulated andused as foams. Pharmaceutical foams include formulations such as, butnot limited to, emulsions, microemulsions, creams, jellies andliposomes. While basically similar in nature these formulations vary inthe components and the consistency of the final product.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

Dosing and administration regimes are tailored by the clinician, orothers skilled in the pharmacological arts, based upon well-knownpharmacological and therapeutic considerations including, but notlimited to, the desired level of therapeutic effect, and the practicallevel of therapeutic effect obtainable. Generally, it is advisable tofollow well-known pharmacological principles for administratingchemotherapeutic agents (e.g., it is generally advisable to not changedosages by more than 50% at time and no more than every 3-4 agenthalf-lives). For compositions that have relatively little or nodose-related toxicity considerations, and where maximum efficacy isdesired, doses in excess of the average required dose are not uncommon.This approach to dosing is commonly referred to as the “maximal dose”strategy. In certain embodiments, the compounds are administered to asubject at a dose of about 0.01 mg/kg to about 200 mg/kg, morepreferably at about 0.1 mg/kg to about 100 mg/kg, even more preferablyat about 0.5 mg/kg to about 50 mg/kg. When the compounds describedherein are co-administered with another agent (e.g., as sensitizingagents), the effective amount may be less than when the agent is usedalone. Dosing may be once per day or multiple times per day for one ormore consecutive days.

Methods of Treatment

The present disclosure provides compounds and methods for inhibiting theactivity of NSD1, NSD2 or NSD3. In certain embodiments, the disclosureprovides compounds that bind to and/or inhibit NSD1, NSD2 or NSD3activity.

Inhibition of NSD1 activity may be assessed and demonstrated by a widevariety of ways known in the art. Non-limiting examples include measure(a) a direct decrease in NSD1 activity; (b) a decrease in cellproliferation and/or cell viability; (c) an increase in celldifferentiation; (d) a decrease in the levels of downstream targets ofNSD1 activity; and (e) decrease in tumor volume and/or tumor volumegrowth rate. Kits and commercially available assays can be utilized fordetermining one or more of the above.

The disclosure provides compounds and methods for treating a subjectsuffering from a disease, comprising administering a compound or saltdescribed herein, for example, a compound or salt of any of Formulas(I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, to the subject. Incertain embodiments, the disease is selected from a disease associatedwith NSD1 expression (e.g., aberrant expression, overexpression, etc.)and/or activity (e.g., cancer). In certain embodiments, the disease ismediated by NSD1 activity and/or expression (e.g., aberrant expression,overexpression, etc.). In certain embodiments, the disease is leukemia,hematologic malignancies, solid tumor cancer, glioma, other cancers,etc.

In some embodiments, the disclosure provides a method for treatingcancer in a subject, comprising administering a compound or saltdescribed herein, for example, a compound or salt of any of Formulas(I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, to the subject. Insome embodiments, the cancer is mediated by a NSD1 expression (e.g.,aberrant expression, overexpression, etc.) and/or activity. In certainembodiments, the cancer is leukemia, breast cancer, prostate cancer,pancreatic cancer, lung cancer, thyroid cancer, liver cancer, skincancer, or a brain tumor.

In certain embodiments, the disclosure provides method of treating adisease in a subject, wherein the the method comprises determining ifthe subject has an NSD1-mediated condition (e.g., cancer) andadministering to the subject a therapeutically effective dose of acompound or salt described herein, for example, a compound or salt ofany one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein.

In some embodiments, NSD1 expression (e.g., aberrant expression,overexpression, etc.) and/or activity has been identified inhematological malignancies, e.g., cancers that affect blood, bone marrowand/or lymph nodes. Accordingly, certain embodiments are directed toadministration of a compound or salt described herein, for example, acompound or salt of any of any one of Formulas (I), (IIa), (IIb), (IIc),(IId), (IIe), (III) or (IV), with any suitable substituents andfunctional groups disclosed herein, to a subject with a hematologicalmalignancy. Such malignancies include, but are not limited to, leukemiasand lymphomas. For example, the presently disclosed compounds can beused for treatment of diseases such as ALL, AML, Chronic lymphocyticleukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenousleukemia (CML), Acute monocytic leukemia (AMoL), hairy cell leukemia,and/or other leukemias. In certain embodiments, the compounds or saltsof the disclosure can be used for treatment of lymphomas such as allsubtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.

Determining whether a tumor or cancer expresses (e.g., overexpresses,aberrantly expresses, etc.) NSD1 can be undertaken by assessing thenucleotide sequence encoding NSD1 or by assessing the amino acidsequence of NSD1. Methods for detecting an NSD1 nucleotide sequence areknown by those of skill in the art. These methods include, but are notlimited to, polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) assays, polymerase chain reaction-single strandconformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCRsequencing, mutant allele-specific PCR amplification (MASA) assays,direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. Methods for detecting an NSD1 protein are known by those ofskill in the art. These methods include, but are not limited to,detection using a binding agent, e.g., an antibody, specific for NSD1,protein electrophoresis and Western blotting, and direct peptidesequencing.

Methods for determining whether a tumor or cancer expresses (e.g.,overexpresses, aberrantly expresses, etc.) NSD1 or is mediated by NSD1activity can use a variety of samples. In some embodiments, the sampleis taken from a subject having a tumor or cancer. In some embodiments,the sample is taken from a subject having a cancer or tumor. In someembodiments, the sample is a fresh tumor/cancer sample. In someembodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

In certain embodiments, the disclosure provides a method of inhibitingNSD1 activity in a sample, comprising administering the compound or saltdescribed herein to said sample comprising NSD1.

The disclosure provides methods for treating a disease by administeringa compound or salt of any one of Formulas (I), (IIa), (IIb), (IIc),(IId), (IIe), (III) or (IV), with any suitable substituents andfunctional groups disclosed herein, to a subject suffering from thedisease, wherein the compound binds NSD1 and/or inhibits NSD1 activity.In certain embodiments, the compound covalently binds to NSD1. Incertain embodiments, the compound noncovalently binds to NSD1.

The disclosure also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to the mammal atherapeutically effective amount of a compound or salt of any one ofFormulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with anysuitable substituents and functional groups disclosed herein. In someembodiments, the method relates to the treatment of cancer such as acutemyeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma,anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, or Viral-Induced cancer. In some embodiments, the methodrelates to the treatment of a non-cancerous hyperproliferative disordersuch as benign hyperplasia of the skin, e.g., psoriasis, restenosis, orprostate, e.g., benign prostatic hypertrophy (BPH). In some cases, themethod relates to the treatment of leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, e.g., castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, livercancer, e.g., hepatocellular carcinoma, or diabetes.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,stereoisomer, isotopologue, hydrate or derivative of the compounds,according to the methods of this invention include, for example,subjects that have been diagnosed as having acute myeloid leukemia,acute myeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma,anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, Viral-Induced cancer, leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma,hepatocellular carcinoma, liver cancer, or diabetes. In some embodimentssubjects that are treated with the compounds of the invention includesubjects that have been diagnosed as having a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin,e.g., psoriasis, restenosis, or prostate, e.g., benign prostatichypertrophy (BPH).

The invention further provides methods of inhibiting NSD1 activity, bycontacting the NSD1 with an effective amount of a compound or salt ofany one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein (e.g., by contacting a cell, tissue, or organ that expressesNSD1). In some embodiments, the invention provides methods of inhibitingNSD1 activity in subject including but not limited to rodents andmammals, e.g., humans, by administering into the subject an effectiveamount of a compound or salt of any one of Formulas (I), (IIa), (IIb),(IIc), (IId), (IIe), (III) or (IV), with any suitable substituents andfunctional groups disclosed herein. In some embodiments, the percentageinhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the disclosure provides methods of inhibiting NSD1activity in a cell by contacting the cell with an amount of a compoundof the invention sufficient to inhibit the activity. In someembodiments, the invention provides methods of inhibiting NSD1 activityin a tissue by contacting the tissue with an amount of a compound orsalt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein, sufficient to inhibit the NSD1 activity in the tissue.In some embodiments, the invention provides methods of inhibiting NSD1activity in an organism (e.g., mammal, human, etc.) by contacting theorganism with an amount of a compound or salt of any one of Formulas(I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein, sufficient toinhibit the NSD1 activity in the organism.

The compositions containing the compounds or salts thereof describedherein can be administered for prophylactic and/or therapeutictreatments. In therapeutic applications, the compositions areadministered to a patient already suffering from a disease, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease. Amounts effective for this use will depend on the severity andcourse of the disease, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingclinician.

In prophylactic applications, compositions containing the compounds orsalts thereof described herein are administered to a patient susceptibleto or otherwise at risk of a particular disease, disorder or condition.Such an amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingclinician.

In the case wherein the patient's condition does not improve, upon theclinician's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease.

In the case wherein the patient's status does improve, upon theclinician's discretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease andits severity, the identity (e.g., weight) of the subject or host in needof treatment, but can nevertheless be determined in a manner recognizedin the field according to the particular circumstances surrounding thecase, including, e.g., the specific agent being administered, the routeof administration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment will typically be in the range of about 0.02-about 5000 mg perday, in some embodiments, about 1-about 1500 mg per day. The desireddose may conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Therapies

Provided herein are methods for combination therapies in which an agentknown to modulate other pathways, or other components of the samepathway, or even overlapping sets of target enzymes are used incombination with a compound or salt of any one of Formulas (I), (IIa),(IIb), (IIc), (IId), (IIe), (III) or (IV), with any suitablesubstituents and functional groups disclosed herein. In one aspect, suchtherapy includes but is not limited to the combination of one or morecompounds of the invention with chemotherapeutic agents, targetedagents, therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

In general, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of theclinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundor salt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein, is nausea, then it may be appropriate to administer ananti-nausea agent in combination with the initial therapeutic agent. Or,by way of example only, the therapeutic effectiveness of one of thecompounds described herein may be enhanced by administration of anadjuvant (i.e., by itself the adjuvant may have minimal therapeuticbenefit, but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient may be increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In any case, regardless of the disease,disorder or condition being treated, the overall benefit experienced bythe patient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

The particular choice of compounds used will depend upon the diagnosisand judgment of the condition of the patient and the appropriatetreatment protocol. The compounds may be administered concurrently(e.g., simultaneously, essentially simultaneously or within the sametreatment protocol) or sequentially, depending upon the nature of thedisease, disorder, or condition, the condition of the patient, and theactual choice of compounds used. The determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is well within theknowledge of the clinician after evaluation of the disease being treatedand the condition of the patient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature. Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease beingtreated and so forth. In addition, when co-administered with one or morebiologically active agents, the compound provided herein may beadministered either simultaneously with the biologically activeagent(s), or sequentially. If administered sequentially, the attendingphysician will decide on the appropriate sequence of administeringprotein in combination with the biologically active agent(s).

In any case, the multiple therapeutic agents (one of which is a compoundor salt of any one of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe),(III) or (IV), with any suitable substituents and functional groupsdisclosed herein, may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease, andthe timing of administering the composition containing a compound canvary. Thus, for example, the compounds can be used as a prophylactic andcan be administered continuously to subjects with a propensity todevelop conditions or diseases in order to prevent the occurrence of thedisease. The compounds and compositions can be administered to a subjectduring or as soon as possible after the onset of the symptoms. Theadministration of the compounds can be initiated within the first 48hours of the onset of the symptoms, preferably within the first 48 hoursof the onset of the symptoms, more preferably within the first 6 hoursof the onset of the symptoms, and most preferably within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over about 5 minutes to about 5 hours, a pill, acapsule, transdermal patch, buccal delivery, and the like, orcombination thereof. A compound is preferably administered as soon as ispracticable after the onset of a disease is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from 1 day to about 3 months. The length of treatmentcan vary for each subject, and the length can be determined using theknown criteria. For example, the compound or a formulation containingthe compound can be administered for at least 2 weeks, preferably about1 month to about 5 years.

Particularly when the compounds and pharmaceutical compositions hereinare used for treating cancer, they may be co-administered with one ormore chemotherapeutics. Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds herein. Insome embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, topoisomerase inhibitors, protein-proteininteraction inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

Embodiments herein further relate to methods for using a compound orsalt of any of Formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or(IV), with any suitable substituents and functional groups disclosedherein, or pharmaceutical compositions provided herein, in combinationwith radiation therapy for inhibiting abnormal cell growth or treatingthe hyperproliferative disorder in the mammal. Techniques foradministering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions herein are also used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (e.g., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments are used inthe form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) or as solvates(e.g., hydrates) to optimize the activity and/or stability of themedicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Other suitable therapeutic agents for coadministration with compoundsherein also include agents for pain and inflammation such as histamineand histamine antagonists, bradykinin and bradykinin antagonists,5-hydroxytryptamine (serotonin), lipid substances that are generated bybiotransformation of the products of the selective hydrolysis ofmembrane phospholipids, eicosanoids, prostaglandins, thromboxanes,leukotrienes, aspirin, nonsteroidal anti-inflammatory agents,analgesic-antipyretic agents, agents that inhibit the synthesis ofprostaglandins and thromboxanes, selective inhibitors of the induciblecyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2,autacoids, paracrine hormones, somatostatin, gastrin, cytokines thatmediate interactions involved in humoral and cellular immune responses,lipid-derived autacoids, eicosanoids, β-adrenergic agonists,ipratropium, glucocorticoids, methylxanthines, sodium channel blockers,opioid receptor agonists, calcium channel blockers, membrane stabilizersand leukotriene inhibitors.

Additional therapeutic agents contemplated for co-administration withcompounds and compositions herein include diuretics, vasopressin, agentsaffecting the renal conservation of water, rennin, angiotensin, agentsuseful in the treatment of myocardial ischemia, anti-hypertensiveagents, angiotensin converting enzyme inhibitors, β-adrenergic receptorantagonists, agents for the treatment of hypercholesterolemia, andagents for the treatment of dyslipidemia.

Other therapeutic agents contemplated for co-administration withcompounds and compositions herein include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundherein include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentinvention with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present invention withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentinvention with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present invention with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present invention with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound hereinare found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein may be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds herein will be co-administered with other agents as describedabove. When used in combination therapy, the compounds described hereinare administered with the second agent simultaneously or separately.This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound of the inventionand any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the invention and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

In some embodiments, a compound described herein is co-administered withanother therapeutic agent effective in treating leukemia and/or othercancers. In some embodiments, a compound described herein isco-administered with one or more therapeutic agents approved for thetreatment of Acute Lymphoblastic Leukemia (ALL), for example: ABITREXATE(Methotrexate), ADRIAMYCIN PFS (Doxorubicin Hydrochloride), ADRIAMYCINRDF (Doxorubicin Hydrochloride), ARRANON (Nelarabine), AsparaginaseErwinia chrysanthemi, CERUBIDINE (Daunorubicin Hydrochloride), CLAFEN(Cyclophosphamide), CLOFARABINE, CLOFAREX (Clofarabine), CLOLAR(Clofarabine), Cyclophosphamide, Cytarabine, CYTOSAR-U (Cytarabine),CYTOXAN (Cyclophosphamide), Dasatinib, Daunorubicin Hydrochloride,Doxorubicin Hydrochloride, Erwinaze (Asparaginase Erwinia Chrysanthemi),FOLEX (Methotrexate), FOLEX PFS (Methotrexate), GLEEVEC (ImatinibMesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, MARQIBO(Vincristine Sulfate Liposome), Methotrexate, METHOTREXATE LPF(Methorexate), MEXATE (Methotrexate), MEXATE-AQ (Methotrexate),Nelarabine, NEOSAR (Cyclophosphamide), ONCASPAR (Pegaspargase),Pegaspargase, Ponatinib Hydrochloride, RUBIDOMYCIN (DaunorubicinHydrochloride), SPRYCEL (Dasatinib), TARABINE PFS (Cytarabine), VINCASARPFS (Vincristine Sulfate), Vincristine Sulfate, etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of AcuteMyeloid Leukemia (AML), for example: ADRIAMYCIN PFS (DoxorubicinHydrochloride), ADRIAMYCIN RDF (Doxorubicin Hydrochloride), ArsenicTrioxide, CERUBIDINE (Daunorubicin Hydrochloride), CLAFEN(Cyclophosphamide), Cyclophosphamide, Cytarabine, CYTOSAR-U(Cytarabine), CYTOXAN (Cyclophosphamide), Daunorubicin Hydrochloride,Doxorubicin Hydrochloride, NEOSAR (Cyclophosphamide), RUBIDOMYCIN(Daunorubicin Hydrochloride), RYDAPT (Midostaurin), TARABINE PFS(Cytarabine), TRISENOX (Arsenic Trioxide), VINCASAR PFS (VincristineSulfate), Vincristine Sulfate, etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of ChronicLymphocytic Leukemia (CLL), for example: Alemtuzumab, AMBOCHLORIN(Chlorambucil), AMBOCLORIN (Chlorambucil), ARZERRA (Ofatumumab),Bendamustine Hydrochloride, CAMPATH (Alemtuzumab), CHLORAMBUCILCLAFEN(Cyclophosphamide), Cyclophosphamide, CYTOXAN (Cyclophosphamide),FLUDARA (Fludarabine Phosphate), Fludarabine Phosphate, LEUKERAN(Chlorambucil), LINFOLIZIN (Chlorambucil), NEOSAR (Cyclophosphamide),Ofatumumab, TREANDA (Bendamustine Hydrochloride), etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of ChronicMyelogenous Leukemia (CML), for example: BOSULIF (Bosutinib), Bosutinib,CLAFEN (Cyclophosphamide), Cyclophosphamide, Cytarabine, CYTOSAR-U(Cytarabine), CYTOXAN (Cyclophosphamide), Dasatinib, GLEEVEC (ImatinibMesylate), ICLUSIG (Ponatinib Hydrochloride), Imatinib Mesylate, NEOSAR(Cyclophosphamide), Nilotinib, Omacetaxine Mepesuccinate, PonatinibHydrochloride, SPRYCEL (Dasatinib), SYNRIBO (Omacetaxine Mepesuccinate),TARABINE PFS (Cytarabine), TASIGNA (Nilotinib), etc.

In some embodiments, a compound described herein is co-administered withone or more therapeutic agents approved for the treatment of MeningealLeukemia, for example: CYTARABINE, CYTOSAR-U (Cytarabine), TARABINE PFS(Cytarabine), etc.

In some embodiments, a compound described herein is co-administered withone or more alkylating agents (e.g., for the treatment of cancer)selected from, for example, nitrogen mustard N-oxide, cyclophosphamide,ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine,apaziquone, brostallicin, bendamustine, carmustine, estramustine,fotemustine, glufosfamide, mafosfamide, bendamustin, mitolactol,cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin,and satraplatin.

In some embodiments, a compound described herein is co-administered withone or more anti-metabolites (e.g., for the treatment of cancer)selected from, for example, methotrexate, 6-mercaptopurineriboside,mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur,cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabin,5-azacitidine, capecitabine, cladribine, clofarabine, decitabine,eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea,melphalan, nelarabine, nolatrexed, ocfosf[iota]te, disodium premetrexed,pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,vidarabine, vincristine, and vinorelbine;

In some embodiments, a compound described herein is co-administered withone or more hormonal therapy agents (e.g., for the treatment of cancer)selected from, for example, exemestane, Lupron, anastrozole,doxercalciferol, fadrozole, formestane, abiraterone acetate,finasteride, epristeride, tamoxifen citrate, fulvestrant, Trelstar,toremifene, raloxifene, lasofoxifene, letrozole, sagopilone,ixabepilone, epothilone B, vinblastine, vinflunine, docetaxel, andpaclitaxel;

In some embodiments, a compound described herein is co-administered withone or more cytotoxic topoisomerase inhibiting agents (e.g., for thetreatment of cancer) selected from, for example, aclarubicin,doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin,9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin,epimbicin, etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, etc.

In some embodiments, a compound described herein is co-administered withone or more anti-angiogenic compounds (e.g., for the treatment ofcancer) selected from, for example, acitretin, aflibercept, angiostatin,aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninat,cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone,pazopanib, ranibizumab, rebimastat, removab, revlimid, sorafenib,vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, andvitaxin.

In some embodiments, a compound described herein is co-administered withone or more antibodies (e.g., for the treatment of cancer) selectedfrom, for example, trastuzumab, cetuximab, bevacizumab, rituximab,ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept,oregovomab, and alemtuzumab.

In some embodiments, a compound described herein is co-administered withone or more VEGF inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, sorafenib, DAST, bevacizumab, sunitinib, recentin,axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib,pazopanib, and ranibizumab.

In some embodiments, a compound described herein is co-administered withone or more EGFR inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, cetuximab, panitumumab, vectibix, gefitinib,erlotinib, and Zactima.

In some embodiments, a compound described herein is co-administered withone or more HER2 inhibitors (e.g., for the treatment of cancer) selectedfrom, for example, lapatinib, tratuzumab, and pertuzumab; CDK inhibitoris selected from roscovitine and flavopiridol;

In some embodiments, a compound described herein is co-administered withone or more proteasome inhibitors (e.g., for the treatment of cancer)selected from, for example, bortezomib and carfilzomib.

In some embodiments, a compound described herein is co-administered withone or more serine/threonine kinase inhibitors (e.g., for the treatmentof cancer), for example, MEK inhibitors and Raf inhibitors such assorafenib.

In some embodiments, a compound described herein is co-administered withone or more tyrosine kinase inhibitors (e.g., for the treatment ofcancer) selected from, for example, dasatinib, nilotibib, DAST,bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib,aflibercept, telatinib, imatinib mesylate, brivanib alaninate,pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix,gefitinib, erlotinib, lapatinib, tratuzumab, pertuzumab and midostaurin

In some embodiments, a compound described herein is co-administered withone or more androgen receptor antagonists (e.g., for the treatment ofcancer) selected from, for example, nandrolone decanoate,fluoxymesterone, Android, Prostaid, andromustine, bicalutamide,flutamide, apocyproterone, apoflutamide, chlormadinone acetate,Androcur, Tabi, cyproterone acetate, and nilutamide.

In some embodiments, a compound described herein is co-administered withone or more aromatase inhibitors (e.g., for the treatment of cancer)selected from, for example, anastrozole, letrozole, testolactone,exemestane, aminoglutethimide, and formestane.

In some embodiments, a compound described herein is co-administered withone or more other anti-cancer agents including, e.g., alitretinoin,ampligen, atrasentan bexarotene, borte-zomib, bosentan, calcitriol,exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone,1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide,pegaspargase, pentostatin, tazaroten, velcade, gallium nitrate,canfosfamide, darinaparsin, and tretinoin. In a preferred embodiment,the compounds of the present disclosure may be used in combination withchemotherapy (e.g., cytotoxic agents), anti-hormones and/or targetedtherapies such as other kinase inhibitors, mTOR inhibitors andangiogenesis inhibitors.

In embodiments in which the compounds and pharmaceutical compositionsherein are used for the treatment or prevention of non-cancer diseasesand/or conditions, the compounds and pharmaceutical compositions hereinmay be co-administered with therapeutics and/or therapies known in thefield to be appropriate for the treatment of such diseases and/orconditions.

Kits

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes a compound or salt of any ofFormulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (III) or (IV), with anysuitable substituents and functional groups disclosed herein, optionallyin a composition or in combination with another agent as disclosedherein. The container(s) optionally have a sterile access port (forexample the container is an intravenous solution bag or a vial having astopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack, for example, contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Experimental

The examples and preparations provided below further illustrate andexemplify the compounds provided herein and methods of preparing suchcompounds. It is to be understood that the scope of the presentinvention is not limited in any way by the scope of the followingexamples and preparations.

2-bromo-3-(2-chlorophenyl)propanoic acid (159-1). At 0° C., a solutionof tert-butyl nitrite (950 uL, 8 mmol, 2 eq) and copper (II) bromide(1.06 g, 4.8 mmol, 1.2 eq) in ACN (20 mL) was added2-amino-3-(2-chlorophenyl) propanoic acid (796 mg, 4 mmol). Then thereaction mixture was allowed to warm to 25° C. and stirred for 2 hours.Water (20 mL) was added and the reaction mixture was extracted by ethylacetate (3*20 mL). The organic layer was combined and washed with brine(3*10 mL) and dried over anhydrous sodium sulfate. After removal ofsolvent, the crude product (780 mg, yield=75%) was used without furtherpurification into the next step.

4-Methoxy-6-nitrobenzo[d]thiazol-2-amine (159-2). At 5° C., a solutionof bromine (5.57 mL, 110 mmol, 1.1 eq) in acetic acid (50 mL) was addedslowly to an acetic acid solution (200 mL) of 2-methoxy-4-methylaniline(16.8 g, 100 mmol) and ammonium thiocyanate (11.4 g, 150 mmol, 1.5 eq)under vigorous stirring. After the completion of addition, the reactionmixture was allowed to warm to 25° C. and stirred for 16 hours. Then thereaction mixture was heated to 95° C. and stirred at this temperaturefor 30 minutes. After the completion monitored by silica gel TLC, thereaction mixture was poured into ice water and basified to pH=11 withammonium hydroxide (m %=28-30% aqueous solution) under vigorousstirring. Then the suspension was stirred at room temperature for 30minutes. After filtration, the solid obtained was stirred inmethanol/ethyl acetate (v/v=1/1, 200 mL) at room temperature for 1 hour.Then, filtration gave the product (13 g, yield=58%) as a yellow solid.¹H NMR (600 MHz, DMSO-d₆): δ 8.38 (d, J=2.2 Hz, 1H), 8.15 (s, 2H), 7.64(d, J=2.1 Hz, 1H), 3.95 (s, 3H). LRMS m/z 226.0 [M+H]⁺.

2-Amino-6-nitrobenzo[d]thiazol-4-ol (159-3). At −78° C., borontribromide (19 mL, 200 mmol, 5 eq) was slowly added into a suspension of4-methoxy-6-nitrobenzo[d]thiazol-2-amine (9.04 g, 40 mmol) indichloromethane (400 mL) via syringe. Then the reaction mixture wasallowed to warm to 25° C. and stirred at this temperature for 48 hours.After the completion monitored by silica gel TLC, the reaction wascooled to 0° C. and quenched with methanol (50 mL). The solvent wasremoved under vacuum. Then ice water (200 mL) was added under vigorousstirring, ammonium hydroxide (m %=28-30% aqueous solution) was addedtill pH=8. The mixture was extracted with ethyl acetate (3*200 mL) andthe organic layer was dried over anhydrous sodium sulfate. Removal ofall volatiles under vacuum gave the crude product (6.1 g, yield=72%) asa dark yellow solid. Then the crude product was used without furtherpurification into the next step. ¹H NMR (600 MHz, DMSO-d₆) δ: 9.06 (s,2H), 8.33 (s, 1H), 7.65 (s, 1H). LRMS m/z 212.0 [M+H]⁺.

4-((tert-Butyldiphenylsilyl)oxy)-6-nitrobenzo[d]thiazol-2-amine (159-4).At 0° C., tert-butyldiphenylchlorosilane (7.5 mL, 28.8 mmol, 1 eq) wasadded into a dimethylformamide (50 mL) solution of2-amino-6-nitrobenzo[d]thiazol-4-ol (6.1 g, 28.8 mmol) and imidazole(7.8 g, 115 mmol, 4 eq). Then the reaction mixture was allowed to warmto 25° C. and stirred for 5 hours. After the completion monitored bysilica gel TLC the reaction mixture was partitioned with ethyl acetate(200 mL) and water (200 mL). The organic layer was washed with brine(3*50 mL) and dried over anhydrous sodium sulfate. After filtration, thereaction mixture was purified by flash chromatography (silica gel, ethylacetate/hexanes=1/4). The product (8.42 g, yield=65%) was obtained as ayellow solid. ¹H NMR (600 MHz, DMSO-d₆) δ: 8.28 (d, J=2.0 Hz, 1H), 8.17(s, 2H), 7.74 (d, J=6.9 Hz, 4H), 7.51 (t, J=7.3 Hz, 2H), 7.46 (t, J=7.3Hz, 4H), 7.10 (d, J=2.2 Hz, 1H), 1.12 (s, 9H). LRMS m/z 450.1 [M+H]⁺.

tert-Butyl(4-((tert-butyldiphenylsilyl)oxy)-6-nitrobenzo[d]thiazol-2-yl)carbamate(159-5). At 0° C., a solution of4-((tert-butyldiphenylsilyl)oxy)-6-nitrobenzo[d]thiazol-2-amine (8.42mg, 18.8 mmol) in dichloromethane (200 mL) was added triethylamine (5.2mL, 37.6 mmol, 2 eq), 4-dimethylaminopyridine (115 mg, 0.94 mmol, 0.05eq) and di-tert-tutyl dicarbonate (4.5 g, 20.7 mmol, 1.1 eq)successively under vigorous stirring. Then the reaction mixture wasallowed to warm to 25° C. and stirred for 16 hours. After the completionmonitored by silica gel TLC, the reaction mixture was purified withflash chromatography (silica gel, ethyl acetate/hexanes=1/9). Theproduct (7.7 g, yield=75%) was obtained as a pale-white solid. ¹H NMR(600 MHz, DMSO-d₆) δ: 12.23 (s, 1H), 8.56 (d, J=1.9 Hz, 1H), 7.75 (d,J=6.9 Hz, 4H), 7.51 (t, J=7.3 Hz, 2H), 7.46 (t, J=7.3 Hz, 4H), 7.18 (d,J=2.1 Hz, 1H), 1.56 (s, 9H), 1.14 (s, 9H). LRMS m/z 550.2 [M+H]⁺.

tert-Butyl(6-amino-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate(159-6). At 25° C., zinc powder (6.4 g, 100 mmol, 10 eq) and ammoniumchloride (5.4 g, 100 mmol, 10 eq, in 20 mL of water) was addedsuccessively into a solution of tert-butyl(4-((tert-butyldiphenylsilyl)oxy)-6-nitrobenzo[d]thiazol-2-yl)carbamate(5.5 g, 10 mmol) in acetone (100 mL). The reaction mixture was stirredat this temperature for 1 hour. Sodium bicarbonate (saturated aqueoussolution, 50 mL) and ethyl acetate (100 mL) were added. After continuedstirring for 30 minutes, the reaction mixture was then filtered overcelite. The organic layer was washed with brine (3*20 mL) and dried overanhydrous sodium sulfate. Removal of the solvents afforded the product(4.8 g, yield=92%) as a white solid. ¹H NMR (600 MHz, DMSO-d₆) δ: 11.27(s, 1H), 7.76 (d, J=6.8 Hz, 4H), 7.49-7.46 (m, 2H), 7.44 (t, J=7.1 Hz,4H), 6.52 (d, J=1.4 Hz, 1H), 5.94 (d, J=1.4 Hz, 1H), 4.85 (s, 2H), 1.52(s, 9H), 1.08 (s, 9H). LRMS m/z 520.2 [M+H]⁺.

tert-Butyl(6-(2-bromo-3-(2-chlorophenyl)propanamido)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate (159-7). To a solution of tert-butyl(6-amino-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate(630 mg, 1.2 mmol) and N-(3-dimethylaminopropyl)-n′-ethylcarbodiimidehydrochloride (768 mg, 4 mmol) in dichloromethane (10 mL) was added2-bromo-3-(2-chlorophenyl)propanoic acid (crude ˜3 mmol) at 0° C. Thenthe reaction mixture was allowed to warm to 25° C. and stirred for 16hours. After the completion monitored by silica gel TLC, the reactionmixture was partitioned with ethyl acetate (30 mL) and water (30 mL).The organic layer was washed with brine (3*10 mL) and dried overanhydrous sodium sulfate. After removal of all volatiles, the reactionmixture was purified with flash chromatography (silica gel, ethylacetate/hexanes=1/5) to afford the product (630 mg, yield=71%) as anoff-white solid. ¹H NMR (600 MHz, DMSO-d₆) δ: 11.65 (s, 1H), 10.17 (s,1H), 7.85 (d, J=1.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 4H), 7.48 (dd, J=7.6,5.2 Hz, 2H), 7.44 (t, J=7.1 Hz, 4H), 7.32-7.20 (m, 3H), 6.73 (d, J=1.7Hz, 1H), 4.73 (t, J=7.5 Hz, 1H), 3.46 (dd, J=14.1, 8.0 Hz, 1H),3.34-3.31 (m, 1H), 1.54 (s, 9H), 1.10 (s, 9H). LRMS m/z 764.1 [M+H]⁺.

N-(2-Amino-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)-2-bromo-3-(2-chlorophenyl)propanamide (159-8). At 25° C., trifluoro acetic acid (6 mL) wasadded into a solution of tert-butyl(6-(2-bromo-3-(2-chlorophenyl)propanamido)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate (650 mg, 0.85 mmol) in dichloromethane(30 mL). Then the reaction mixture was stirred for 6 hours. After thecompletion monitored by silica gel TLC, sodium bicarbonate (saturatedaqueous solution) was added to neutralize the reaction mixture. Theorganic layer was dried over anhydrous sodium sulfate. Removal of thesolvents afforded the product (560 mg, yield=99%) as a yellow solid. ¹HNMR (600 MHz, DMSO-d₆) δ: 10.00 (s, 1H), 7.75 (d, J=6.8 Hz, 4H), 7.63(d, J=1.7 Hz, 1H), 7.49-7.46 (m, 2H), 7.43 (dd, J=8.9, 5.3 Hz, 5H), 7.31(s, 2H), 7.29-7.25 (m, 1H), 7.23 (d, J=6.2 Hz, 1H), 7.22-7.18 (m, 1H),6.59 (d, J=1.6 Hz, 1H), 4.71 (t, J=7.5 Hz, 1H), 3.45 (dd, J=14.1, 8.0Hz, 1H), 3.30 (dd, J=14.1, 6.9 Hz, 1H), 1.08 (s, 9H). LRMS m/z 664.1[M+H]⁺.

N⁶-(2-bromo-3-(2-chlorophenyl)propyl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole-2,6-diamine(159-9). At 0° C., borane-tetrahydrofuran complex (44.5 mL, 1 M intetrahydrofuran, 10 eq) was added into a solution ofN-(2-amino-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)-2-bromo-3-(2-chlorophenyl)propanamide (2.95 g, 4.45 mmol) in tetrahydrofuran (100 mL). Thereaction mixture was allowed to warm to 25° C. and stirred for 16 hours.After the completion monitored by LC-MS, the reaction mixture was cooledto 0° C. Under vigorous stirring, methanol (10 mL) and saturated aqueoussolution of ammonium chloride (20 mL) were added dropwise. The mixturewas then partitioned with ethyl acetate (100 mL) and water (50 mL), theorganic layer was washed with brine (3*20 mL) and dried over anhydroussodium sulfate. The product (2.8 g, yield=96%) was obtained after thefiltration and removal of all volatiles. The crude product was obtainedas an off-white solid and used into the next step without furtherpurification. LRMS m/z 650.1 [M+H]⁺.

4-((tert-Butyldiphenylsilyl)oxy)-6-(2-(2-chlorobenzyl)aziridin-1-yl)benzo[d]thiazol-2-amine(159-10). At 25° C., cesium carbonate (2.8 g, 8.6 mmol, 2 eq) andpotassium iodide (250 mg, 1.5 mmol, 0.35 eq) were added into a solutionofN⁶-(2-bromo-3-(2-chlorophenyl)propyl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole-2,6-diamine(2.8 g, 4.3 mmol) in acetonitrile (150 mL). Then the reaction mixturewas heated to 75° C. and stirred for 4 hours. After the completionmonitored by LC-MS, the solvent was removed under vacuum. The reactionmixture was partitioned with ethyl acetate (50 mL) and water (50 mL),the organic layer was washed with brine (3*20 mL) and dried overanhydrous sodium sulfate. After removal of all volatiles, the reactionmixture was purified with flash chromatography (silica gel, ethylacetate/hexanes=1/4) to afford the product (250 mg, yield=62%) as awhite solid. LC-MS m/z 570.2 [M+H]⁺.

2-Amino-6-(2-(2-chlorobenzyl)aziridin-1-yl)benzo[d]thiazol-4-ol (159).At 0° C., tetrabutylammonium fluoride (2.63 mL, 2.63 mmol, 1 M intetrahydrofuran) was added into a solution of4-((tert-butyldiphenylsilyl)oxy)-6-(2-(2-chlorobenzyl)aziridin-1-yl)benzo[d]thiazol-2-amine(1.5 g, 2.63 mmol) in tetrahydrofuran (10 mL). Then the reaction mixturewas stirred at this temperature for 15 minutes. After the completionmonitored by LC-MS, methanol (2 mL) was added and the reaction mixturewas purified with flash chromatography (silica gel,methanol/dichloromethane=1/9) to afford the product (550 mg, yield=63%)as a white solid. ¹H NMR (600 MHz, DMSO-d₆) δ: 9.11 (s, 1H), 7.53-7.44(m, 2H), 7.37-7.28 (m, 2H), 6.98 (s, 2H), 6.55 (d, J=1.9 Hz, 1H), 6.17(d, J=1.9 Hz, 1H), 3.02 (dd, J=14.1, 6.0 Hz, 1H), 2.92 (dd, J=13.9, 5.5Hz, 1H), 2.35-2.27 (m, 1H), 2.09 (d, J=3.0 Hz, 1H), 2.03 (d, J=6.2 Hz,1H). ¹³C NMR (151 MHz, DMSO-d₆) δ: 162.75 (s), 147.36 (s), 136.77 (s),136.60 (s), 133.03 (s), 132.01 (s), 131.49 (s), 129.17 (s), 128.31 (s),127.28 (s), 105.11 (s), 102.55 (s), 40.09 (s), 36.16 (s), 33.23 (s).HRMS (ESI) m/z calcd: C₁₆H₁₅ClN₃OS [M+H]⁺ 332.0619; found, 332.0620.

tert-Butyl 7-nitro-1H-indole-1-carboxylate (163-1). At 0° C., a solutionof 7-nitroindole (1.22 g, 7.5 mmol) in dichloromethane (20 mL) was addedtriethylamine (2.08 mL, 15 mmol, 2 eq), 4-dimethylaminopyridine (46 mg,0.38 mmol, 0.05 eq) and di-tert-butyl dicarbonate (1.64 g, 7.5 mmol, 1eq) under vigorous stirring. Then the reaction mixture was allowed towarm to 25° C. and stirred for 1 hour. After the completion monitored byTLC, the reaction mixture was purified with flash chromatography (ethylacetate/hexanes=1/10). The product was obtained (1.79 g, yield=91%) ofwas obtained as a yellow solid. LRMS m/z 263.1 [M+H]⁺.

tert-Butyl 7-amino-1H-indole-1-carboxylate (163-2). At 25° C., zincpowder (1.28 g, 20 mmol, 10 eq) and ammonium chloride (1.08 mg, 20 mmol,10 eq, in 4 mL of water) was added successively into a solution oftert-butyl 7-nitro-1H-indole-1-carboxylate (524 mg, 2 mmol) in acetone(20 mL). Then the reaction mixture was stirred at this temperature for30 minutes. After the completion monitored by TLC, the reaction mixturewas filtered through celite. Methanol was removed under vacuum to give aresidue which was then partitioned with ethyl acetate (30 mL) and water(30 mL). The organic layer was washed with brine (3*10 mL) and driedover anhydrous sodium sulfate. The product (450 mg, yield=97%) wasobtained as a colorless gum and used without further purification intothe next step. LRMS m/z 233.1 [M+H]⁺.

2,4-Dibromo-6-methoxyaniline (163-3). At 5° C., a solution of bromine(9.8 mL, 192.5 mmol, 1.1 eq) in dichloromethane (120 mL) was addedslowly to a dichloromethane solution (240 mL) of4-bromo-2-methoxyaniline (35.35 g, 175 mmol) under vigorous stirring.The reaction mixture was kept at this temperature for 2 h. After thecompletion monitored by TLC, the reaction mixture was poured into icewater and extracted with ethyl acetate (3*200 mL). The organic layer wascombined, washed with brine (3*50 mL) and dried over sodium sulfate.Then the reaction mixture was purified by flash column chromatography(ethyl acetate/hexanes (v/v) =5/95). The product (40.3 g, yield=82%) wasobtained as a red liquid. ¹H NMR (600 MHz, CDCl₃) δ 7.20 (d, J=1.9 Hz,1H), 6.84 (d, J=1.8 Hz, 1H), 4.21 (s, 2H), 3.86 (s, 3H). LRMS m/z 280.0[M+H]⁺.

1-(2,4-Dibromo-6-methoxyphenyl)thiourea (163-5). At 0° C.,benzoylchloride (11.8 mL, 102.1 mmol, 1.1 eq) was added slowly into asuspension of ammonium thiocyanate (7.76 g, 102.1 mmol, 1.1 eq) inacetone (150 mL). The reaction mixture was allowed to warm to 25° C. andstirred for 1 hour. Then, 2,4-dibromo-6-methoxyaniline (26 g, 92.8 mmol)was added and the reaction mixture was stirred for another 1 hour. Afterthe completion monitored by TLC, water (150 mL) was added, the reactionmixture was stirred for another 15 minutes. The precipitation formed wasfiltered and washed with water (3*50 mL) to afford a light yellow solid.The solid was then added into an aqueous solution of sodium hydroxide(14.85 g, 371.2 mmol, in 150 mL water). The resulting reaction mixturewas then stirred at 80° C. for 3 hours. The reaction mixture was cooled,conc. HCl (aq) was added to pH=1. After that, ammonium hydroxide (30%w/w, aq) was added to pH=10 and the mixture were stirred at 10° C. for30 minutes. The precipitate was filtered, washed with water (25 mL) togive crude compound. The crude product was dried in air and a yellowsolid (30.4 g, yield=96%) was obtained and used without furtherpurification into the next step. LRMS m/z 338.9 [M+H]⁺.

6-Bromo-4-methoxybenzo[d]thiazol-2-amine (163-6). At 0° C.,1-(2,4-dibromo-6-methoxyphenyl)thiourea (20 g, 59 mmol) was added to astirred suspension of sodium hydride (4.72 g, 118 mmol, 2 eq) in1-methyl-2-pyrrolidinone (100 mL). Then the reaction mixture was heatedto 150° C. and stirred for 10 min After the completion monitored by TLC,the reaction mixture was cooled in an ice bath. Saturated aqueousammonium chloride solution was added to neutralize the reaction mixture.The reaction mixture was extracted with ethyl acetate (3*500 mL). Theorganic layer was washed with brine (3*100 mL). After removing allvolatiles, the residue was stirred in ethyl acetate/hexanes (v/v=1/10)for 30 minutes. Then, filtration afforded the product as yellow solid(28 g, yield=92%) and used without further purification into the nextstep. LRMS m/z 259.0 [M+H]⁺.

2-Amino-6-bromobenzo[d]thiazol-4-ol (163-7). At 0° C., boron tribromide(21.1 mL, 222 mmol, 5 eq) was slowly added into a suspension of6-bromo-4-methoxybenzo[d]thiazol-2-amine (11.5 g, 20 mmol) indichloromethane (300 mL) via syringe. Then the reaction mixture wasallowed to warm to 25° C. and stirred for 16 h. After the completionmonitored by TLC, methanol (50 mL) was added slowly at 0° C. to quenchthe reaction. Saturated aqueous sodium bicarbonate was added until pH=6.The suspension was filtered and the filtrate was extracted with ethylacetate (3*200 mL). The solid and the organic layer were combined andall volatiles were removed under vacuum. Then, the residue was stirredin ethyl acetate/hexanes (v/v=1/10, 200 mL) for 30 minutes. Afterfiltration, the product (10.5 g, yield=97%) was obtained as a yellowsolid and used without further purification into the next step. ¹H NMR(600 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.72 (s, 2H), 7.49 (d, J=1.1 Hz,1H), 6.99 (d, J=1.0 Hz, 1H). LRMS m/z 245.0 [M+H]⁺.

6-Bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (163-8).At 0° C., tert-butyldiphenylchlorosilane (1.9 mL, 7.3 mmol, 1 eq) wasadded into a dimethylformamide (10 mL) solution of2-amino-6-bromobenzo[d]thiazol-4-ol (1.8 g, 7.3 mmol) and imidazole(1.98 g, 29.2 mmol, 4 eq). Then the reaction mixture was allowed to warmto 25° C. and stirred for 2 hours. The mixture was partitioned withethyl acetate (30 mL) and water (30 mL), then the organic layer waswashed with brine (3*10 mL) and dried over anhydrous sodium sulfate. Thereaction mixture was purified by flash chromatography (ethylacetate/hexanes (v/v) =1/4) to afford the product (2.48 g, yield=70%) ayellow solid. LRMS m/z 483.0 [M+H]⁺.

2-Di-tert-butoxycarbonylamino-6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole (163-9).At 0° C., a solution of6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (2.6 g,5.4 mmol), triethylamine (1.5 mL, 10.8 mmol, 2 eq) and4-dimethylaminopyridine (33 mg, 0.27 mmol, 0.05 eq) in dichloromethane(20 mL) was added a dichloromethane (20 mL) solution of di-tert-tutyldicarbonate (2.36 g, 10.8 mmol, 2 eq) dropwise under vigorous stirring.Then the reaction mixture was allowed to warm to 25° C. and stirred for1 hour. The reaction mixture was purified with flash chromatography(ethyl acetate/hexanes (v/v) =1/10). The product (3 g, yield=81%) wasobtained as a yellow solid. LRMS m/z 683.2 [M+H]⁺.

2-(Di-tert-butoxycarbonylamino)-4-((tert-butyldiphenylsilyl)oxy)-6-(3-hydroxyprop-1-yn-1-yl)benzo[d]thiazole(163-10). At 25° C., copper (I) iodide (210 mg, 1.1 mmol, 0.10 eq) wasadded to a mixture of 2-di-tert-butoxycarbonylamino-6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole (3.6 g,5.3 mmol), prop-2-yn-1-ol (1.5 mL, 26.5 mmol, 5 eq) andtetrakis(triphenylphosphine) palladium(0) (1.27 g, 1.1 mmol, 0.10 eq) intriethylamine (15 mL). Then the reaction mixture was heated to 80° C.and stirred at this temperature for 4 hours. After the completionmonitored by TLC, the reaction mixture was filtered over celite andpartitioned with ethyl acetate (10 mL) and water (10 mL). The organiclayer was washed with brine (3*5 mL) and dried over anhydrous sodiumsulfate. The reaction mixture was purified by flash columnchromatography (ethyl acetate/hexanes (v/v) =1/4) to afford the product(2.43 g, yield=70%) as a yellow solid. LRMS m/z 659.2 [M+H]⁺.

3-(2-((Di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-ylmethanesulfonate (163-11). At 0° C., diisopropylethylamine (198 uL, 1.2mmol, 1.1 eq) was added to a dichloromethane (8 mL) solution of2-(di-tert-butoxycarbonylamino)-4-((tert-butyldiphenylsilyl)oxy)-6-(3-hydroxyprop-1-yn-1-yl)benzo[d]thiazole(700 mg, 1.06 mmol). Then, a dichloromethane (2 mL) solution ofmethylsulfonyl chloride (93 uL, 1.2 mmol, 1.1 eq) was added slowly intothe reaction mixture. The reaction mixture was allowed to warm to 25° C.and stirred at this temperature for 1 hour. After the completionmonitored by TLC, all volatiles were removed to give a residue. Thecrude product (700 mg, yield=90%) was obtained as a yellow gum and usedwithout further purification into the next step.

tert-Butyl7-((3-(2-((di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)-1H-indole-1-carboxylate(163-12). A solution of3-(2-((di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-ylmethanesulfonate (270 mg, 0.37 mmol) and tert-butyl7-amino-1H-indole-1-carboxylate (258 mg, 1.11 mmol, 3 eq) inacetonitrile (2 mL) was stirred at 25° C. for 2 days. After thecompletion monitored by TLC, the reaction mixture was separated withpartitioned with ethyl acetate (10 mL) and water (10 mL). The organiclayer was washed with brine (3*5 mL) and dried over anhydrous sodiumsulfate. The reaction mixture was purified by flash chromatography(ethyl acetate/hexanes=1/10 to 1/0). The product (160 mg, yield=47%) wasobtained as a yellow gum. LRMS m/z 873.4 [M+H]⁺.

6-(3-((1H-Indol-7-yl)amino)prop-1-yn-1-yl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine(163-13). At 25° C., trifluoroacetic acid (1 mL) was added into asolution of tert-butyl7-((3-(2-((di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)-1H-indole-1-carboxylate(150 mg, 0.17 mmol) in dichloromethane (5 mL). Then the reaction mixturewas stirred for 16 h. Saturated aqueous sodium bicarbonate solution wasadded to neutralize the reaction mixture. The reaction mixture was thenpartitioned with ethyl acetate (20 mL) and water (20 mL). The organiclayer was washed with brine (3*10 mL) and dried over sodium sulfate. Theproduct (70 mg, yield=71%) was obtained as an off-white solid. LRMS m/z573.2 [M+H]⁺.

6-(3-((1H-Indol-7-yl)amino)prop-1-yn-1-yl)-2-aminobenzo[d]thiazol-4-ol(163).6-(3-((1H-Indol-7-yl)amino)prop-1-yn-1-yl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine(70 mg, 0.12 mmol) was dissolved in a methanol solution of ammonia (7 Min methanol, 2 mL). Then the reaction mixture was stirred at 25° C. for16 h. The reaction mixture was purified by flash chromatography(methanol/dichloromethane=1/10). The product (15 mg, yield=37%) wasobtained as an off-white solid. ¹H NMR (600 MHz, DMSO-d₆) δ 10.66 (s,1H), 9.41 (s, 1H), 7.39 (s, 2H), 7.25 (t, J=2.6 Hz, 1H), 7.17 (d, J=1.1Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.85 (t, J=7.6 Hz, 1H), 6.66 (s, 1H),6.40 (d, J=7.4 Hz, 1H), 6.36-6.32 (m, 1H), 5.69 (t, J=5.8 Hz, 1H), 4.26(d, J=5.8 Hz, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.66 (s), 147.14 (s),142.00 (s), 133.64 (s), 132.14 (s), 127.81 (s), 125.50 (s), 123.64 (s),119.88 (s), 115.03 (s), 114.55 (s), 109.61 (s), 101.57 (s), 101.44 (s),85.99 (s), 82.85 (s), 33.24 (s). HRMS (ESI) m/z calcd: C₁₈H₁₅N₄OS [M+H]⁺335.0961; found, 335.0965.

tert-Butyl (3-(vinylsulfonamidomethyl)phenyl)carbamate (199-1). In a dryvial tert-butyl (3-(aminomethyl)phenyl)carbamate (222 mg, 1 mmol) andDIPEA (358 μL, 2 mmol) were dissolved in dry DCM (8 ml) and the solutionwas cooled to 0° C. 2-Chloroethanesulfonyl chloride (105 μL, 1 mmol) inDCM (3 mL) was added dropwise. After 2 h all the starting material wasconsumed. The product was directly purified by column chromatography onsilica gel DCM to DCM/MeOH 15:1, affording a pale yellow oil,contaminated with DIPEA. The compound was used for next step as obtainedwithout characterization.

N-(3-aminobenzyl)ethenesulfonamide (199-2). Crude tert-Butyl(3-(vinylsulfonamidomethyl)phenyl)carbamate was dissolved in dry DCM (6ml) and the solution was cooled to 0° C. TFA (2 mL) was added and themixture was left to stir for 3 h. The mixture was evaporated, carefullyneutralized with 7N ammonia in MeOH and the product was directlypurified by column chromatography on silica gel DCM to DCM/MeOH 12:1,affording a pale yellow oil. Yield for two steps: 108 mg, 51%. ¹H NMR(600 MHz, MeOD) δ 7.05 (t, J=7.7 Hz, 1H), 6.71 (s, 1H), 6.64 (dd,J=13.8, 8.0 Hz, 2H), 6.56 (dd, J=16.5, 10.0 Hz, 1H), 6.11 (d, J=16.6 Hz,1H), 5.89 (d, J=10.0 Hz, 1H), 4.02 (s, 2H). ¹³C NMR (151 MHz, MeOD) δ149.0, 139.8, 138.1, 130.2, 126.1, 118.7, 116.0, 115.8, 47.8.

2,4-Dibromo-6-methoxyaniline (199-3). At 5° C., a solution of bromine(9.8 mL, 192.5 mmol, 1.1 eq) in dichloromethane (120 mL) was addedslowly to a dichloromethane solution (240 mL) of4-bromo-2-methoxyaniline (35.35 g, 175 mmol) under vigorous stirring.The reaction mixture was kept at this temperature for 2 h. After thecompletion monitored by TLC, the reaction mixture was poured into icewater and extracted with ethyl acetate (3*200 mL). The organic layer wascombined, washed with brine (3*50 mL) and dried over sodium sulfate.Then the reaction mixture was purified by flash column chromatography(ethyl acetate/hexanes (v/v)=5/95). The product (40.3 g, yield=82%) wasobtained as a red liquid. ¹H NMR (600 MHz, CDCl₃) δ 7.20 (d, J=1.9 Hz,1H), 6.84 (d, J=1.8 Hz, 1H), 4.21 (s, 2H), 3.86 (s, 3H). LRMS m/z 280.0[M+H]⁺.

1-(2,4-Dibromo-6-methoxyphenyl)thiourea (199-4, 199-5). At 0° C.,benzoylchloride (11.8 mL, 102.1 mmol, 1.1 eq) was added slowly into asuspension of ammonium thiocyanate (7.76 g, 102.1 mmol, 1.1 eq) inacetone (150 mL). The reaction mixture was allowed to warm to 25° C. andstirred for 1 hour. Then, 2,4-dibromo-6-methoxyaniline (26 g, 92.8 mmol)was added and the reaction mixture was stirred for another 1 hour. Afterthe completion monitored by TLC, water (150 mL) was added, the reactionmixture was stirred for another 15 minutes. The precipitation formed wasfiltered and washed with water (3*50 mL) to afford a light yellow solid.The solid was then added into an aqueous solution of sodium hydroxide(14.85 g, 371.2 mmol, in 150 mL water). The resulting reaction mixturewas then stirred at 80° C. for 3 hours. The reaction mixture was cooled,conc. HCl (aq) was added to pH=1. After that, ammonium hydroxide (30%w/w, aq) was added to pH=10 and the mixture were stirred at 10° C. for30 minutes. The precipitate was filtered, washed with water (25 mL) togive crude compound. The crude product was dried in air and a yellowsolid (30.4 g, yield=96%) was obtained and used without furtherpurification into the next step. LRMS m/z 338.9 [M+H]⁺.

6-Bromo-4-methoxybenzo[d]thiazol-2-amine (199-6). At 0° C.,1-(2,4-dibromo-6-methoxyphenyl)thiourea (20 g, 59 mmol) was added to astirred suspension of sodium hydride (4.72 g, 118 mmol, 2 eq) in1-methyl-2-pyrrolidinone (100 mL). Then the reaction mixture was heatedto 150° C. and stirred for 10 min After the completion monitored by TLC,the reaction mixture was cooled in an ice bath. Saturated aqueousammonium chloride solution was added to neutralize the reaction mixture.The reaction mixture was extracted with ethyl acetate (3*500 mL). Theorganic layer was washed with brine (3*100 mL). After removing allvolatiles, the residue was stirred in ethyl acetate/hexanes (v/v=1/10)for 30 minutes. Then, filtration afforded the product as yellow solid(28 g, yield=92%) and used without further purification into the nextstep. LRMS m/z 259.0 [M+H]⁺.

2-Amino-6-bromobenzo[d]thiazol-4-ol (199-7). At 0° C., boron tribromide(21.1 mL, 222 mmol, 5 eq) was slowly added into a suspension of6-bromo-4-methoxybenzo[d]thiazol-2-amine (11.5 g, 20 mmol) indichloromethane (300 mL) via syringe. Then the reaction mixture wasallowed to warm to 25° C. and stirred for 16 h. After the completionmonitored by TLC, methanol (50 mL) was added slowly at 0° C. to quenchthe reaction. Saturated aqueous sodium bicarbonate was added until pH=6.The suspension was filtered and the filtrate was extracted with ethylacetate (3*200 mL). The solid and the organic layer were combined andall volatiles were removed under vacuum. Then, the residue was stirredin ethyl acetate/hexanes (v/v=1/10, 200 mL) for 30 minutes. Afterfiltration, the product (10.5 g, yield=97%) was obtained as a yellowsolid and used without further purification into the next step. ¹H NMR(600 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.72 (s, 2H), 7.49 (d, J=1.1 Hz,1H), 6.99 (d, J=1.0 Hz, 1H). LRMS m/z 245.0 [M+H]⁺.

6-Bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (199-8).At 0° C., tert-butyldiphenylchlorosilane (1.9 mL, 7.3 mmol, 1 eq) wasadded into a dimethylformamide (10 mL) solution of2-amino-6-bromobenzo[d]thiazol-4-ol (1.8 g, 7.3 mmol) and imidazole(1.98 g, 29.2 mmol, 4 eq). Then the reaction mixture was allowed to warmto 25° C. and stirred for 2 hours. The mixture was partitioned withethyl acetate (30 mL) and water (30 mL), then the organic layer waswashed with brine (3*10 mL) and dried over anhydrous sodium sulfate. Thereaction mixture was purified by flash chromatography (ethylacetate/hexanes (v/v) =1/4) to afford the product (2.48 g, yield=70%) ayellow solid. LRMS m/z 483.0 [M+H]⁺.

2-Di-tert-butoxycarbonylamino-6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole (199-9).At 0° C., a solution of6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (2.6 g,5.4 mmol), triethylamine (1.5 mL, 10.8 mmol, 2 eq) and4-dimethylaminopyridine (33 mg, 0.27 mmol, 0.05 eq) in dichloromethane(20 mL) was added a dichloromethane (20 mL) solution of di-tert-tutyldicarbonate (2.36 g, 10.8 mmol, 2 eq) dropwise under vigorous stirring.Then the reaction mixture was allowed to warm to 25° C. and stirred for1 hour. The reaction mixture was purified with flash chromatography(ethyl acetate/hexanes (v/v) =1/10). The product (3 g, yield=81%) wasobtained as a yellow solid. LRMS m/z 683.2 [M+H]⁺.

2-(Di-tert-butoxycarbonylamino)-4-((tert-butyldiphenylsilyl)oxy)-6-(3-hydroxyprop-1-yn-1-yl)benzo[d]thiazole(199-10). At 25° C., copper (I) iodide (210 mg, 1.1 mmol, 0.10 eq) wasadded to a mixture of 2-di-tert-butoxycarbonylamino-6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole (3.6 g,5.3 mmol), prop-2-yn-1-ol (1.5 mL, 26.5 mmol, 5 eq) andtetrakis(triphenylphosphine) palladium(0) (1.27 g, 1.1 mmol, 0.10 eq) intriethylamine (15 mL). Then the reaction mixture was heated to 80° C.and stirred at this temperature for 4 hours. After the completionmonitored by TLC, the reaction mixture was filtered over celite andpartitioned with ethyl acetate (10 mL) and water (10 mL). The organiclayer was washed with brine (3*5 mL) and dried over anhydrous sodiumsulfate. The reaction mixture was purified by flash columnchromatography (ethyl acetate/hexanes (v/v) =1/4) to afford the product(2.43 g, yield=70%) as a yellow solid. LRMS m/z 659.2 [M+H]⁺.

3-(2-((Di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-ylmethanesulfonate (199-11). At 0° C., diisopropylethylamine (198 uL, 1.2mmol, 1.1 eq) was added to a dichloromethane (8 mL) solution of2-(di-tert-butoxycarbonylamino)-4-((tert-butyldiphenylsilyl)oxy)-6-(3-hydroxyprop-1-yn-1-yl)benzo[d]thiazole(700 mg, 1.06 mmol). Then, a dichloromethane (2 mL) solution ofmethylsulfonyl chloride (93 uL, 1.2 mmol, 1.1 eq) was added slowly intothe reaction mixture. The reaction mixture was allowed to warm to 25° C.and stirred at this temperature for 1 hour. After the completionmonitored by TLC, all volatiles were removed to give a residue. Thecrude product (700 mg, yield=90%) was obtained as a yellow gum and usedwithout further purification into the next step.

tert-butyl(4-((tert-butyldiphenylsilyl)oxy)-6-(3-((3-(vinylsulfonamidomethyl)phenyl)amino)prop-1-yn-1-yl)benzo[d]thiazol-2-yl)carbamate(199-12). The crude 199-11 (mixture of mono- and diBoc compounds, around0.08 mmol) was dissolved in MeCN (2 mL).N-(3-aminobenzyl)ethenesulfonamide (51 mg, 0.24 mmol) was added and themixture was left to stir at rt for 72 h. LC-MS showed only traces of thestarting material. The product was directly purified by columnchromatography on silica gel (DCM to DCM/MeOH 20:1). The obtainedcompound was deprotected without characterization.

N-(3-((3-(2-amino-4-hydroxybenzo[d]thiazol-6-yl)prop-2-yn-1yl)amino)benzyl)ethenesulfonamide (199). Crude 199-12 was dissolved indry DCM (2 mL) and TFA (0.7 mL) was added at 0° C. After 6 h the mixturewas fully concentrated, carefully neutralized with 7N ammonia solutionin methanol and concentrated again. The crude compound was dissolved inTHF (1.5 mL) and 1M TBAF solution in THF (0.2 mL) was added at 0° C.Both steps were monitored by LC-MS. After full deprotection the mixturewas concentrated and the product was directly purified by columnchromatography on silica gel (DCM to DCM/MeOH 10:1) afforded the finalproduct as a white solid. Yield 20 mg, 60% starting from 199-10. ¹H NMR(600 MHz, MeOD) δ 7.12-7.06 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 6.72 (s,1H), 6.63 (dd, J=16.5, 10.0 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 6.15 (d,J=16.6 Hz, 1H), 5.94 (d, J=10.0 Hz, 1H), 4.08 (s, 2H), 3.29 (s, 2H),3.29 (d, J=6.5 Hz, 2H), 2.61 (t, J=6.5 Hz, 2H). ¹³C NMR (151 MHz, MeOD)δ 171.6, 168.8, 149.9, 148.2, 142.3, 140.4, 137.6, 133.2, 130.2, 126.6,118.2, 116.6, 115.8, 111.2, 111.1, 106.7, 86.3, 83.9, 40.2, 38.3, 34.8.HRMS (ESI) calculated C₁₉H₁₉N₄O₃S₂ [M+H]⁺ 415.0899, found 415.0894.

3-(4-(((benzyloxy)carbonyl)amino)phenyl)propanoic acid (197-1).3-(4-Aminophenyl)propanoic acid (412 mg, 2.5 mmol) was dissolved inwater (4 mL). NaOH (340 mg, 8.5 mmol) was added followed by CbzCl (0.46mL, 3.24 mmol) addition at 0° C. After stirring overnight the mixturewas washed with ether, cooled and acidified with 1N HCl to pH 2. Afterstirring for 30 min the product was filtered and dried, affording a paleyellow solid. Yield 359 mg, 48%. LC-MS m/z 300.1 [M+H]⁺

tert-butyl(3-(3-(4-(((benzyloxy)carbonyl)amino)phenyl)propanamido)phenyl)carbamate(197-2). To a solution of3-(4-(((benzyloxy)carbonyl)amino)phenyl)propanoic acid (359 mg, 1.2mmol) in 6 mL of DCM were added HATU (383 mg, 1 mmol), DIPEA (536 μL,2.5 mmol) and tert-butyl (3-aminophenyl)carbamate (208 mg, 1 mmol).After stirring for 12 h at room temperature, LC-MS showed fullconversion. The mixture was diluted with water, extracted 3 times withDOA, concentrated and the product was directly purified by columnchromatography on silica gel DCM to DCM/MeOH 20:1 affording a colorlessoil that turned solid in the fridge. Used without characterization.LC-MS m/z 490.2 [M+H]⁺

tert-butyl (3-(3-(4-aminophenyl)propanamido)phenyl)carbamate (197-3).The 0.03M solution of tert-butyl(3-(3-(4-(((benzyloxy)carbonyl)amino)phenyl)propanamido)phenyl)carbamatein MeOH was pumped through the system with 10%Pd/C catalyst (1 mL/min)at 60° C., 2 bar, until LC-MS showed full conversion. The solution wasconcentrated and the compound was used as obtained withoutcharacterization. LC-MS m/z 355.2 [M+H]⁺

tert-butyl (3-(3-(4-acrylamidophenyl)propanamido)phenyl)carbamate(197-4) Acryloyl chloride (0.16 mL, 2 mmol, 2 equiv) was added to astirred suspension of potassium carbonate (0.28 g, 2 mmol, 2 equiv) indistilled water (0.5 mL) and acetone (2 mL) at 0° C. under an atmosphereof nitrogen, and then tert-butyl(3-(3-(4-aminophenyl)propanamido)phenyl)carbamate (crude, max. 1 mmol inacetone (1 mL) was added dropwise into the mixture. The suspension wasstirred at 0° C., and monitored by TLC. After filtration, the mixturewas concentrated under reduced pressure and extracted with EtOAc. Theorganic layer was dried over MgSO₄, and concentrated, affording a whitesolid. Used as obtained. LC-MS m/z 410.2 [M+H]⁺

N-(4-(3-((3-aminophenyl)amino)-3-oxopropyl)phenyl)acrylamide (197-5).Crude tert-butyl (3-(3-(4-acrylamidophenyl)propanamido)phenyl)carbamatewas dissolved in dry DCM (9 ml) and the solution was cooled to 0° C. TFA(3 mL) was added and the mixture was left to stir for 3 h. The mixturewas evaporated carefully neutralized with ammonia in MeOH and theproduct was directly purified by column chromatography on silica gel DCMto DCM/MeOH 12:1, affording a white crystalline solid. Yield 210 mg,0.68 mmol, 68% for last 3 steps. ¹H NMR (600 MHz, MeOD) δ 7.53 (d, J=8.0Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.02-6.97 (m, 2H), 6.76 (d, J=7.5 Hz,1H), 6.46 (d, J=7.2 Hz, 1H), 6.44-6.38 (m, 2H), 6.34 (dd, J=16.9, 1.5Hz, 1H), 5.74 (dd, J=10.0, 1.4 Hz, 1H), 2.96 (t, J=7.4 Hz, 2H), 2.62 (t,J=7.6 Hz, 2H). ¹³C NMR (151 MHz, MeOD) δ 173.5, 166.1, 149.3, 140.4,138.5, 137.9, 132.5, 130.3, 129.8, 127.6, 121.6, 112.7, 111.4, 108.6,39.8, 32.3.

tert-butyl(6-(3-((3-(3-(4-acrylamidophenyl)propanamido)phenyl)amino)prop-1-yn-1-yl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate(197-6). The crude 199-11 (mixture of mono- and diBoc compounds, around0.08 mmol) was dissolved in MeCN (2 mL).N-(3-aminobenzyl)ethenesulfonamide (51 mg. 0.24 mmol) was added and themixture was left to stir at rt for 72 h. LC-MS showed only traces of thestarting material. The product was directly purified by columnchromatography on silica gel (DCM to DCM/MeOH 20:1). The obtainedcompound was deprotected without characterization.

N-(4-(3-((3-((3-(2-amino-4-hydroxybenzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)phenyl)amino)-3-oxopropyl)phenyl)acrylamide(197). Crude tert-butyl(6-(3-((3-(3-(4-acrylamidophenyl)propanamido)phenyl)amino)prop-1-yn-1-yl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate(197-6) was dissolved in dry DCM (2 mL) and TFA (0.7 mL) was added at 0°C. After 6 h the mixture was fully concentrated, carefully neutralizedwith 7N ammonia solution in methanol and concentrated again. The crudecompound was dissolved in THF (1.5 mL) and 1M TBAF solution in THF (0.2mL) was added at 0° C. Both steps were monitored by LC-MS. After fulldeprotection the mixture was concentrated and the product was directlypurified by column chromatography on silica gel (DCM to DCM/MeOH 10:1)afforded the final product as a white solid. Yield 20 mg, 49% startingfrom 199-10. ¹H NMR (600 MHz, MeOD) δ 7.52 (d, J=7.9 Hz, 2H), 7.21 (d,J=8.0 Hz, 2H), 7.11 (s, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.81(d, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.52 (d, J=7.8 Hz, 1H), 6.43-6.30 (m,2H), 5.73 (d, J=9.9 Hz, 1H), 4.07 (s, 2H), 2.96 (t, J=7.4 Hz, 2H), 2.62(t, J=7.4 Hz, 2H). ¹³C NMR (151 MHz, MeOD) δ 173.6, 168.8, 166.1, 149.9,148.2, 142.3, 140.4, 138.5, 137.8, 133.2, 132.5, 130.2, 129.8, 127.6,121.6, 118.3, 116.6, 115.8, 111.2, 111.1, 106.8, 86.3, 83.9, 39.8, 34.8,32.3. HRMS (ESI) calculated C₂₈H₂₆N₅O₃S [M+H]⁺ 512.1756, found 512.1752.

tert-butyl (3-(acrylamidomethyl)phenyl)carbamate (237-1). In a dry vialtert-butyl (3-(aminomethyl)phenyl)carbamate (290 mg, 1.3 mmol) and DIPEA(330 μL, 1.9 mmol) were dissolved in dry DCM (9 ml) and the solution wascooled to 0° C. Acryloyl chloride (114 μL, 1.4 mmol) in DCM (2 mL) wasadded dropwise. After 2 h all the starting material was consumed. Theproduct was directly purified by column chromatography on silica gel DCMto DCM/MeOH 12:1, affording a pale yellow oil. The compound wasdeprotected without characterization. LRMS m/z 277.2 [M+H]⁺.

N-(3-aminobenzyl)acrylamide (237-2). Crude tert-butyl(3-(acrylamidomethyl)phenyl)carbamate was dissolved in dry DCM (6 ml)and the solution was cooled to 0° C. TFA (2 mL) was added and themixture was left to stir for 4 h. The mixture was evaporated, carefullyneutralized with 7N ammonia in MeOH and the product was directlypurified by column chromatography on silica gel DCM to DCM/EtOAc 1:9,affording a white solid. Yield 190 mg, 1.18 mmol, 83% for 2 steps. LRMSm/z 177.1 [M+H]⁺. ¹H NMR (600 MHz, MeOD) δ 7.05 (t, J=7.7 Hz, 1H), 6.66(s, 1H), 6.63-6.60 (m, 2H), 6.31-6.20 (m, 2H), 5.66 (dd, J=9.4, 2.6 Hz,1H), 4.34 (s, 2H). ¹³C NMR (151 MHz, MeOD) δ 168.0, 149.0, 140.5, 132.1,130.3, 126.7, 118.4, 115.7, 115.5, 44.3.

2,4-Dibromo-6-methoxyaniline (237-3). 4-bromo-2-methoxyaniline (25 g;124 mmol) was dissolved in DCM (375 mL) and cooled to 0° C. Bromine (6.4mL, 124 mmol) in DCM (50 mL) was added dropwise. The mixture was stirredat room temperature overnight. The reaction mixture was washed withwater and saturated Na₂CO₃ solution and the product was directlyisolated by column chromatography on silica gel (Hex to Hex/EtOAc 15:1)yielding an orange oil that turned solid in the fridge. Yield 28.36 g,101.29 mmol, 82%. ¹H NMR (600 MHz, CDCl₃) δ 7.20 (d, J=1.9 Hz, 1H), 6.84(d, J=1.8 Hz, 1H), 4.21 (s, 2H), 3.86 (s, 3H). LRMS m/z 280.0 [M+H]⁺.

N-((2,4-dibromo-6-methoxyphenyl)carbamothioyl)benzamide (237-4). Benzoylchloride (12.36 mL, 106.35 mmol) and ammonium thiocyanate (8.47 g,111.42 mmol) were dissolved in extra dry acetone (250 mL) and mixturewas left to stir for 1 h. After that 2,4-dibromo-6-methoxyaniline (28.36g, 101.29 mmol) was added and the stirring was continued for 2 h. Water(350 mL) was slowly added. The precipitate was filtered, washed withwater and hexane/ether 1:1 mixture. The obtained white solid was usedwithout additional purification and characterization. LRMS m/z 442.9[M+H]⁺.

1-(2,4-Dibromo-6-methoxyphenyl)thiourea (237-5). CrudeN-((2,4-dibromo-6-methoxyphenyl)carbamothioyl)benzamide was added to asolution of NaOH (10 g in 140 mL of water). The resulting reactionmixture was stirred at 80° C. for 3 h. The reaction mixture was cooled,conc. HCl was slowly added to pH=1. After that, conc. aqueous NH₃ wasadded to pH=10 and the mixture were stirred at 10° C. for 30 min. Theprecipitate was filtered, washed with water and hexane/ether 1:1 mixtureaffording a white solid. Yield 31.93 g, 98 mmol, 97% for 2 steps. LRMSm/z 338.9 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d6): δ 8.89 (s, 1H), 7.44 (s,1H), 7.28 (s, 1H), 6.70-7.70 (br s, 2H), 3.80 (s, 3H). ¹³C NMR (150 MHz,DMSO-d6): δ 171.3, 157.7, 131.1, 128.1, 127.3, 126.0, 115.1, 56.5.

6-Bromo-4-methoxybenzo[d]thiazol-2-amine (237-6). To a stirredsuspension of NaH (60% in mineral oil, 5.88 g, 147 mmol) in NMP (140 mL)at 0° C. was slowly added 1-(2,4-dibromo-6-methoxyphenyl)thiourea (31.93g, 98 mmol). The reaction mixture was heated up to 160° C. for 2 h. Thereaction mixture was cooled in an ice bath. Water was added and themixture was extracted 3 times with EtOAc. The combined organics waswashed 2 times with brine and concentrated. The solid was suspended inether/hexane mixture and filtered, yielding a creamy solid. NMR showedaround 50% demethylation. Was used for full demethylation as obtained.Yield 14.07 g, around 52.7 mmol, 72%. LRMS m/z 259.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): δ 7.48 (br s+s, 3H), 6.96 (d, J=1.5 Hz, 1H), 3.84 (s,3H). ¹³C NMR (150 MHz, DMSO-d₆): δ 165.8, 150.1, 141.4, 133.2, 115.7,112.3, 111.4, 56.1.

2-Amino-6-bromobenzo[d]thiazol-4-ol (237-7). To a solution of partiallydemethylated 6-bromo-4-methoxy-1,3-benzothiazol-2-amine (14.07 g, around52.7 mmol) in dry DCM (600 mL), was cooled to 0° C. and Boron tribromide(25.5 mL, 5 equiv.) was added. The reaction mixture was stirredovernight at rt. LC-MS showed full conversion. The reaction mixture wascooled to 0° C. and slowly quenched with methanol (250 mL). The mixturewas concentrated to around 100-200 mL and neutralized with aqueoussaturated solution of NaHCO₃. After extraction with EtOAc (3 times) theproduct was concentrated, suspended in Hex/EtOAc 20:1 mixture, stirredfor 15 min and filtered affording an off-white solid. Yield 10.59 g. Thefiltrate was concentrated and suspended in Hex/ether 15:1 mixture. Thesecond batch was collected. Total yield 12.46 g, 51.06 mmol, 97%. LRMSm/z 245.0 [M+H]⁺. ¹H NMR (600 MHz, MeOD) δ 7.21 (d, J=1.8 Hz, 1H), 6.84(d, J=1.8 Hz, 1H). ¹³C NMR (151 MHz, MeOD) δ 168.1, 149.4, 141.2, 134.5,115.8, 115.4, 114.9.

6-Bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (237-8).A TBDPSCl (8.07 mL, 31 mmol) solution in DMF (30 mL) was added dropwiseto a solution of alcohol (7.4 g, 28.9 mmol 8.1 mmol) and imidazole (4.08g, 60 mmol) in dry DMF (145 mL) at 0° C. under argon. The reactionmixture was stirred at room temperature overnight. The mixture wasdiluted by water and extracted 3 times with EtOAc. The combined organicswas washed with water and brine and dried over MgSO₄. The crude productwas purified by column chromatography on silica gel (Hex to Hex/EtOAc4:1) affording a white solid. Yield 11.28 g, 23.41 mmol, 81%. LRMS m/z483.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.78 (dd, J=8.1, 1.3 Hz, 4H),7.47-7.43 (m, 2H), 7.39 (t, J=7.3 Hz, 4H), 7.23 (d, J=1.8 Hz, 1H), 6.63(d, J=1.8 Hz, 1H), 5.72 (br s, 2H), 1.19 (s, 9H). ¹³C NMR (151 MHz,CDCl₃) δ 164.8, 146.9, 143.2, 135.7, 134.0, 133.0, 130.2, 127.9, 119.9,116.5, 114.0, 27.1, 20.0.

2-Di-tert-butoxycarbonylamino-6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazole (237-9).6-bromo-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-amine (7.1 g,14.7 mmol) was dissolved in dry DCM (70 mL). The mixture was cooled to0° C. and TEA (6.15 mL, 44.2 mmol), DMAP (90 mg, 0.74 mmol) and Bocanhydride (9.64 g, 44.2 mmol) were added. The mixture was allowed towarm to rt and stirred overnight. The mixture was concentrated and theproduct was isolated by column chromatography on silica gel (slowgradient Hex to Hex/EtOAc 10:1) affording a white solid. Yield 7.3 g,10.69 mmol, 73%. LRMS m/z 683.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.77(dd, J=8.0, 1.3 Hz, 4H), 7.47-7.42 (m, 2H), 7.42-7.37 (m, J=12.7, 4.4Hz, 5H), 6.49 (d, J=1.8 Hz, 1H), 1.60 (s, 18H), 1.16 (s, 9H). ¹³C NMR(151 MHz, CDCl₃) δ 156.4, 149.5, 149.0, 141.0, 136.0, 135.8, 132.5,130.3, 128.0, 119.7, 116.6, 116.3, 85.5, 28.0, 26.8, 19.9.

2-(Di-tert-butoxycarbonylamino)-4-((tert-butyldiphenylsilyl)oxy)-6-(3-hydroxyprop-1-yn-1-yl)benzo[d]thiazole(237-10). At 25° C., CuI (305 mg, 1.6 mmol, 0.15 eq) was added to amixture of starting material (7.3 g, 10.69 mmol), prop-2-yn-1-ol (3.05mL, 53 mmol, 5 eq) and Pd(PPh₃)₄ (1.85 g, 1.6 mmol, 0.15 eq) in TEA (105mL). Then the reaction mixture was heated to 80° C. and stirred at thistemperature for 4 h. The mixture was diluted with water, filteredthrough Celite layer and extracted with EtOAc. The product was directlyisolated by column chromatography on silica gel (DCM to DCM/EtOAc 6:1)yielding a white solid. Yield 4.53 g, 6.88 mmol, 64%. LRMS m/z 659.2[M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.78-7.75 (m, 4H), 7.42 (t, J=7.4 Hz,2H), 7.38-7.34 (m, 5H), 6.48 (d, J=1.2 Hz, 1H), 4.33 (s, 2H), 1.60 (s,18H), 1.14 (s, 9H). ¹³C NMR (151 MHz, CDCl₃) δ 157.4, 149.5, 148.2,142.3, 135.8, 134.9, 132.7, 130.1, 127.9, 119.2, 118.5, 117.6, 86.8,85.6, 85.5, 51.7, 28.0, 26.8, 19.9.

3-(2-((Di-tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-ylmethanesulfonate (237-11). To a DCM solution of the starting material(53 mg; 0.08 mmol/1 mL) DIPEA (15 μL; 0.085 mmol) was added. Thereaction mixture was cooled to 0° C. and mesyl chloride (7.5 μL, 0.085mmol) in DCM (0.2 mL) was added dropwise. Reaction was allowed to stirfor 1 hr at 0° C. LC-MS showed full conversion. The reaction wasquenched with water, aq. NH₄Cl solution was added and the mixture wasextracted 3 times with EtOAc. Combined organic layer was dried withMgSO₄ and concentrated at rt. The obtained crude mesylate was used rightaway without purification and characterization. LRMS m/z 737.2 [M+H]⁺.

tert-butyl(6-(3-((3-(acrylamidomethyl)phenyl)amino)prop-1-yn-1-yl)-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-2-yl)carbamate(237-12). The crude mesylate (presumed 0.08 mmol) was dissolved in MeCN(0.5 mL). N-(3-aminobenzyl)acrylamide (42 mg, 0.32 mmol) and were addedand the mixture was left to stir at rt for 72 h. LC-MS showed theproduct and only traces of the starting material. The product wasdirectly purified by column chromatography on silica gel (DCM toDCM/EtOAc 10:1) and deprotected without characterization. LRMS m/z 717.3[M+H]⁺. One Boc proup was partially lost during purification. Compoundname and LRMS correspond to mono-Boc compound.

N-(3-((3-(2-amino-4-hydroxybenzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)benzyl)acrylamide(237). The crude material was dissolved in dry DCM (2 mL) and TFA (1 mL)was added at 0° C. After stirring for 4 hours the mixture wasconcentrated, carefully neutralized with 7N ammonia in methanol andconcentrated again. 1 mL of THF and 1M THF solution of TBAF (0.16 mL)were added. After 4 h the compound was fully deprotected. The mixturewas concentrated and the product was directly isolated by columnchromatography on silica gel (DCM to DCM/MeOH 12:1), affording a whitesolid. Yield 21 mg, 0.047 mmol, 59% for 3 steps. ¹H NMR (600 MHz, DMSO)δ 9.39 (s, 1H), 8.48 (s, 1H), 7.38 (s, 2H), 7.13 (s, 1H), 7.08 (t, J=7.7Hz, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.57 (d, J=7.9 Hz, 1H), 6.52 (d,J=7.2 Hz, 1H), 6.28 (dd, J=17.1, 10.2 Hz, 1H), 6.12 (d, J=17.1 Hz, 1H),6.04 (t, J=5.5 Hz, 1H), 5.59 (d, J=10.2 Hz, 1H), 4.26 (d, J=5.3 Hz, 2H),4.06 (d, J=5.8 Hz, 2H). ¹³C NMR (151 MHz, DMSO) δ 165.6, 164.4, 148.0,147.1, 141.9, 139.7, 132.1, 131.7, 128.8, 125.1, 115.7, 115.1, 115.0,114.5, 112.0, 111.1, 86.0, 82.4, 42.5, 32.9. HRMS (ESI) calc. forC₂₀H₁₉N₄O₂S (M+H)⁺ 379.1229, found 379.1228.

N-(2,4-dimethoxybenzyl)ethenesulfonamide (288-1). At 0° C.,triethylamine (1.1 mL, 8 mmol, 4 eq) was added to a DCM (6 mL) solutionof (2, 4-dimethoxyphenyl) methanamine (300 uL, 2 mmol). Then,2-chloroethane-1-sulfonyl chloride (210 uL, 2 mmol, 1 eq) was added intothe reaction mixture. The reaction mixture was allowed to warm to 25° C.and stirred at this temperature for 16 hours. The reaction mixture waspartitioned with dichloromethane (10 mL) and water (10 mL). The organiclayer was washed with brine (10 mL) and dried over anhydrous sodiumsulfate. The reaction mixture was purified by silica gel flashchromatography (ethyl acetate/hexanes=1/4). The product (400 mg,yield=78%) was obtained as a colorless gum. ¹H NMR (600 MHz, DMSO-d₆) δ7.45 (d, J=5.6 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.62 (dd, J=16.6, 10.0Hz, 1H), 6.53 (d, J=2.1 Hz, 1H), 6.50 (dd, J=8.3, 2.2 Hz, 1H), 6.01 (d,J=16.6 Hz, 1H), 5.92 (d, J=10.0 Hz, 1H), 3.95 (d, J=5.9 Hz, 2H).

3-(3-(trimethylsilyl)prop-2-yn-1-yl)benzaldehyde (288-2). To a solutionof 3-(bromomethyl)benzaldehyde (1 g, 5 mmol), copper (I) iodide (950 mg,5 mmol,1 eq), cesium carbonate (1.8 g, 5.5 mmol, 1.1 eq), andtetrabutylammonium iodide (1.85 g, 5 mmol, 1 eq) in dry acetonitrile (20mL) was added (trimethylsilyl)acetylene (2.11 mL, 15 mmol, 3 eq). Themixture was stirred at 75° C. for 24 hours. The reaction mixture wasquenched with saturated aqueous ammonium chloride solution (50 mL) andextracted with ethyl acetate (3*20 mL). The organic layers were washedwith brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo and purified by column chromatographyon silica gel (ethyl acetate/hexanes=1/4). The product (900 mg,yield=83%) was obtained as a colorless liquid. ¹H NMR (600 MHz, DMSO-d₆)δ 10.03-9.99 (m, 1H), 7.88-7.85 (m, 1H), 7.82-7.78 (m, 1H), 7.64 (s,1H), 7.61-7.56 (m, 1H), 3.85 (d, J=7.1 Hz, 1H), 0.19-0.15 (m, 1H).

(3-(3-(trimethylsilyl)prop-2-yn-1-yl)phenyl)methanol (288-3). Sodiumborohydride (676 mg, 17.78 mmol, 4 eq) was added to a methanol (20 mL)solution of 288-2 (960 mg, 4.44 mmol), and the resulting mixture wasstirred for 5 hours at room temperature. The reaction mixture wasquenched with saturated aqueous ammonium chloride solution (20 mL) andthen partitioned with ethyl acetate (50 mL) and water (50 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate and then concentrated under vacuum. The crude product (960 mg,yield=99%) was obtained as a yellow liquid and used without furtherpurification into the next step. ¹H NMR (600 MHz, DMSO-d₆) δ 7.30-7.25(m, 2H), 7.18 (d, J=7.5 Hz, 2H), 5.14 (t, J=5.6 Hz, 1H), 4.48 (d, J=5.4Hz, 2H), 3.68 (s, 2H), 0.15 (s, 9H).

(3-(prop-2-yn-1-yl)phenyl)methanol (288-4). 288-3 (960 mg, 4.4 mmol) wasdissolved in methanol (75 mL). Potassium fluoride (2.55 g, 44 mmol, 10eq) was added and the reaction was stirred for 24 h at 45° C. Aftercooling to room temperature the reaction was quenched by addition ofwater (100 mL) and ethyl acetate (100 mL). The aqueous layer wasextracted with ethyl acetate (3*50 mL), the combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The resulting crude product (600 mg, yield=93%) was obtained as acolorless liquid and used without further purification into the nextstep.

2-Di-tert-butoxycarbonylamino-(4-((tert-butyldiphenylsilyl)oxy)-6-(3-(3-(hydroxymethyl)phenyl)prop-1-yn-1-yl)benzo[d]thiazole(288-5). At 25° C., copper (I) iodide (19 mg, 0.1 mmol, 0.1 eq) wasadded to a mixture of 163-9 (683 mg, 1 mmol), 288-4 (292 mg, 2 mmol, 2eq) and Pd(PPh₃)₄ (116 mg, 0.1 mmol, 0.1 eq) in triethylamine (5 mL).Then the reaction mixture was heated to 85° C. and stirred at thistemperature for 4 hours. The reaction mixture was partitioned with water(20 mL) and ethyl acetate (20 mL). The organic layer was washed withbrine (10 mL) and dried over anhydrous sodium sulfate. The reactionmixture was purified by flash column chromatography. The product (85 mg,yield=12%) was obtained as a white solid (ethyl acetate/hexanes=1/2).LRMS m/z 749.3 [M+H]⁺.

2-Di-tert-butoxycarbonylamino-(4-((tert-butyldiphenylsilyl)oxy)-6-(3-(3-((N-(2,4-dimethoxybenzyl)vinylsulfonamido)methyl)phenyl)prop-1-yn-1-yl)benzo[d]thiazole)(288-6). At 0° C., to a tetrahydrofuran (3 mL) solution of 288-1 (120mg, 0.16 mmol), 288-5 (41 mg, 0.16 mmol, 1 eq) and triphenylphosphine(63 mg, 0.24 mmol, 1.5 eq) was added DIAD (47 uL, 0.24 mmol, 1.5 eq).Then the reaction mixture was allowed to warm to 25° C. and stirred for16 hours. The reaction mixture was purified by flash chromatography(ethyl acetate/hexanes=1/4). The product (80 mg, yield=51%) was obtainedas a white solid. LRMS m/z 988.4 [M+H]⁺.

N-(3-(3-(2-amino-4-((tert-butyldiphenylsilyl)oxy)benzo[d]thiazol-6-yl)prop-2-yn-1-yl)benzyl)ethenesulfonamide(288-7). At 0° C., trifluoroacetic acid (1 mL) was added slowly into asolution of 288-6 (80 mg, 0.08 mmol) in dichloromethane (2 mL). Then thereaction mixture was allowed to warm to 25° C. and stirred for 2 hours.Saturated aqueous sodium bicarbonate solution was added to neutralizethe reaction mixture. Dichloromethane (5 mL) was added, and the organiclayer was washed with saturated aqueous sodium bicarbonate solution (3*5mL) and dried over sodium sulfate. The reaction mixture was purified byflash chromatography (ethyl acetate/hexanes=1/2). The product (20 mg,yield=31%) was obtained as a colorless gum. LRMS m/z 638.2 [M+H]⁺.

N-(3-(3-(2-amino-4-hydroxybenzo[d]thiazol-6-yl)prop-2-yn-1-yl)benzyl)ethanesulfonamide (288). At 0° C., TBAF (45 uL, 1 M in tetrahydrofuran, 0.045mmol, 1.5 eq) was added into a solution of 288-7 (20 mg, 0.03 mmol) intetrahydrofuran (2 mL). Then the reaction mixture was stirred in icebath for 1 hour. Methanol (2 mL) was added and the reaction mixture waspurified by flash chromatography (ethyl acetate/hexanes=1/2). Theproduct (8 mg, yield=64%) was obtained as a light yellow solid. ¹H NMR(600 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.82 (t, J=5.5 Hz, 1H), 7.41-7.28 (m,4H), 7.22 (d, J=11.2 Hz, 2H), 6.68 (dd, J=16.2, 9.7 Hz, 2H), 6.04 (d,J=16.5 Hz, 1H), 5.93 (d, J=10.0 Hz, 1H), 4.07 (d, J=5.9 Hz, 2H), 3.85(s, 2H).

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1. A composition comprising a compound comprising a structure of:

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein R⁶ is selected from H,alkyl, substituted alkyl, alkene, substituted alkene, hydroxy, alkoxy,amine, alkylamine, alkenamine, aklynamine, thiol, thioalkyl, halogen,ketone, amide, cyano, sulfonyl, thiocyanate, phosphine oxide, acarbocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring,carbocyclic or heterocyclic aromatic ring fused to another aromaticring, a hydrogen bond donor, a hydrogen bond acceptor, and combinationsthereof; and wherein R⁷ is H, D, F, OH, NH₂, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, hydroxy, alkoxy, amine, alkylamine,thioalkyl, halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, acarbocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring,carbocyclic or heterocyclic aromatic ring fused to another aromaticring, a hydrogen bond donor, a hydrogen bond acceptor, and combinationsthereof; wherein R⁴ is selected from H, alkyl, substituted alkyl,hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, haloalkyl,amide, cyano, sulfonyl, phosphine oxide, a hydrogen bond donor, ahydrogen bond acceptor, and combinations thereof; wherein R⁵ is selectedfrom H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, alkylamine,thioalkyl, halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, acarbocyclic ring, an aromatic ring, a substituted aromatic ring, aheterocyclic aromatic ring, a substituted heterocyclic aromatic ring, asubstituted or non-substituted heterocyclic non-aromatic ring,carbocyclic or heterocyclic aromatic ring fused to another aromaticring, a hydrogen bond donor, a hydrogen bond acceptor, and combinationsthereof; wherein L¹ and L² are independently 1-8 member aliphatic carbonlinkers, optionally comprising one or more heteroatoms and/or one ormore double or triple bonds; L¹ or L² may be present or absent; whereinA is an aryl, heteroaryl, cycloalkyl, or heterocycle; wherein A isunsubstituted or substituted; wherein Y is a Michael acceptor; Y may bepresent or absent; wherein R⁷ is H, D, F, OH, NH₂, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein Z is NH, S, O, CH₂, oris absent; wherein A is an aryl, heteroaryl, cycloalkyl, or heterocycle;wherein A is unsubstituted or substituted; wherein L and is a 1-8 memberaliphatic carbon linker, optionally comprising one or more heteroatomsand/or one or more double or triple bonds; L may be present or absent;wherein Y is a Michael; Y may be present or absent; wherein R⁷ is H, D,F, OH, NH, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein Z is NH, S, O, CH₂, oris absent; wherein R⁸ is selected from H, alkyl, substituted alkyl,alkene, substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy,amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide, a carbocyclic ring, an aromatic ring, a substitutedaromatic ring, a heterocyclic aromatic ring, a substituted heterocyclicaromatic ring, a substituted or non-substituted heterocyclicnon-aromatic ring, carbocyclic or heterocyclic aromatic ring fused toanother aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor,and combinations thereof; wherein L is a 1-8 member aliphatic carbonlinker, optionally comprising one or more heteroatoms and/or one or moredouble or triple bonds; wherein Y is a Michael acceptor; wherein R⁷ isH, D, F, OH, NH₂, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein Z is NH, S, O, CH₂, oris absent; wherein A is an aryl, heteroaryl, cycloalkyl, or heterocycle;wherein A is unsubstituted or substituted; wherein L is absent or is a1-8 member aliphatic carbon linker, optionally comprising one or moreheteroatoms and/or one or more double or triple bonds; wherein E is anaryl, heteroaryl, cycloalkyl, or heterocycle; wherein E is unsubstitutedor substituted; wherein Y is a Michael acceptor; wherein R⁷ is H, D, F,OH, NH₂, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein Z is NH, S, O, CH₂, oris absent; wherein R² is selected from H, alkyl, substituted alkyl,alkene, substituted alkene, alkyne, substituted alkene, hydroxy, alkoxy,amine, alkylamine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl,phosphine oxide, a carbocyclic ring, an aromatic ring, a substitutedaromatic ring, a heterocyclic aromatic ring, a substituted heterocyclicaromatic ring, a substituted or non-substituted heterocyclicnon-aromatic ring, carbocyclic or heterocyclic aromatic ring fused toanother aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor,and combinations thereof; wherein L and is a 1-8 member aliphatic carbonlinker, optionally comprising one or more heteroatoms and/or one or moredouble or triple bonds; wherein A is an aryl, heteroaryl, cycloalkyl, orheterocycle; wherein A is unsubstituted or substituted; wherein Y is aMichael acceptor; wherein R⁷ is H, D, F, OH, NH₂, CH₃;

or a salt thereof; wherein X is CH₂ or NH; wherein R² is selected fromH, alkyl, substituted alkyl, alkene, substituted alkene, alkyne,substituted alkene, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR⁴ is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine,alkylamine, thioalkyl, halogen, haloalkyl, amide, cyano, sulfonyl,phosphine oxide, a hydrogen bond donor, a hydrogen bond acceptor, andcombinations thereof; wherein R⁵ is selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen, ketone,amide, cyano, sulfonyl, phosphine oxide, a carbocyclic ring, an aromaticring, a substituted aromatic ring, a heterocyclic aromatic ring, asubstituted heterocyclic aromatic ring, a substituted or non-substitutedheterocyclic non-aromatic ring, carbocyclic or heterocyclic aromaticring fused to another aromatic ring, a hydrogen bond donor, a hydrogenbond acceptor, and combinations thereof; wherein R⁶ is selected from H,alkyl, substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, an aryl ring, a substituted arylring, a heteroaryl ring, a substituted heteroaryl ring, and combinationsthereof; and wherein R⁷ is H, D, F, OH, NH₂, CH₃; and/or

or a salt thereof; wherein X is CH₂ or NH; wherein G is—(CH₂)_(n)—S—S—(CH₂)_(m)—, wherein n and m are independently 0-6;wherein R^(2a) and R^(2b) are independently selected from H, alkyl,substituted alkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl,halogen, ketone, amide, cyano, sulfonyl, phosphine oxide, a carbocyclicring, an aromatic ring, a substituted aromatic ring, a heterocyclicaromatic ring, a substituted heterocyclic aromatic ring, a substitutedor non-substituted heterocyclic non-aromatic ring, carbocyclic orheterocyclic aromatic ring fused to another aromatic ring, a hydrogenbond donor, a hydrogen bond acceptor, and combinations thereof; whereinR^(4a) and R^(4b) are independently selected from H, alkyl, substitutedalkyl, hydroxy, alkoxy, amine, alkylamine, thioalkyl, halogen,haloalkyl, amide, cyano, sulfonyl, phosphine oxide, a hydrogen bonddonor, a hydrogen bond acceptor, and combinations thereof; whereinR^(7a) and R^(7b) are H, D, F, OH, NH₂, CH₃. 2-8. (canceled)
 9. Acomposition of claim 1, wherein the compound selected from Compounds1-311.
 10. A composition of claim 1, wherein R2-R8, Z, A, L, L1, L2, E,Y (present or absent) may comprise any combination of the substituentsdepicted in the compounds 1-311 in any suitable combinations.
 11. Amethod of treating a subject comprising administering to the subject acomposition of claim
 1. 12. The method of claim 11, wherein the subjectsuffers from cancer.
 13. The method of claim 12, wherein the cancer isacute leukemia or breast cancer. 14-16. (canceled)